Substituted-quinoxaline-type piperidine compounds and the uses thereof

ABSTRACT

The invention relates to Substituted-Quinoxaline-Type Piperidine Compounds, compositions comprising an effective amount of a Substituted-Quinoxaline-Type Piperidine Compound and methods to treat or prevent a condition, such as pain, comprising administering to an animal in need thereof an effective amount of a Substituted-Quinoxaline-Type Piperidine Compound.

1. FIELD OF THE INVENTION

The invention relates to Substituted-Quinoxaline-Type PiperidineCompounds, compositions comprising an effective amount of aSubstituted-Quinoxaline-Type Piperidine Compound and methods to treat orprevent a condition, such as pain, comprising administering to an animalin need thereof an effective amount of a Substituted-Quinoxaline-TypePiperidine Compound.

2. BACKGROUND OF THE INVENTION

Chronic pain is a major contributor to disability and is the cause ofmuch suffering. The successful treatment of severe and chronic pain is aprimary goal of the physician, with opioid analgesics being preferreddrugs for doing so.

Until recently, there was evidence of three major classes of opioidreceptors in the central nervous system (CNS), with each class havingsubtype receptors. These receptor classes are known as μ, κ and δ. Asopiates have a high affinity for these receptors while not beingendogenous to the body, research followed in order to identify andisolate the endogenous ligands to these receptors. These ligands wereidentified as endorphins, dynorphins and enkephalins, respectively.

Recent experimentation has led to the identification of a cDNA encodingan opioid receptor-like (ORL-1) receptor with a high degree of homologyto the known receptor classes. The ORL-1 receptor was classified as anopioid receptor based only on structural grounds, as the receptor didnot exhibit pharmacological homology. It was initially demonstrated thatnon-selective ligands having a high affinity for μ, κ and δ receptorshad low affinity for the ORL-1 receptor. This characteristic, along withthe fact that an endogenous ligand had not yet been discovered, led tothe term “orphan receptor”.

Subsequent research led to the isolation and structure of the endogenousligand of the ORL-1 receptor (i.e., nociceptin; also known as orphaninFQ (OFQ)). This ligand is a seventeen amino acid peptide structurallysimilar to members of the opioid peptide family.

The discovery of the ORL-1 receptor presents an opportunity in drugdiscovery for novel compounds that can be administered for painmanagement or other syndromes modulated by this receptor.

International PCT Publication No. WO 99/46260 A1 describes quinoxalinonederivatives as inhibitors of protein kinase C.

International PCT Publication No. WO 99/50254 A1 describes quinoxalinonederivatives as serine protease inhibitors.

International PCT Publication No. WO 01/90102 A2 describes6-heterocyclyl-3-oxo-3,4-dihydro-quinoxalines for use as herbicides.

International PCT Publication No. WO 2005/028451 A1 describestetrahydroquinoxaline derivatives for use as M2 acetylcholine receptoragonists.

International PCT Publication No. WO 2003/062234 A1 describesquinoxaline derivatives for use in remedying diseases in whichpoly(ADP-ribose) polymerase (PARP) participates.

U.S. published patent application No. US 2005/0256000 by Schaper et al.describes quinoxaline-2-one derivatives for use as safeners for plants.

Citation of any reference in Section 2 of this application is not to beconstrued as an admission that such reference is prior art to thepresent application.

3. SUMMARY OF THE INVENTION

It is an object of the invention to provide new compounds that exhibitaffinity for the ORL-1 receptor.

In certain embodiments of the invention, such new compounds exhibitagonist activity at the ORL-1 receptor.

In certain embodiments of the invention, such new compounds exhibitpartial agonist activity at the ORL-1 receptor.

In certain other embodiments of the invention, such new compoundsexhibit antagonist activity at the ORL-1 receptor.

In certain embodiments of the invention, such new compounds exhibitaffinity for the ORL-1 receptor, and also for one or more of the μ, κ orδ receptors. In a particular embodiment, a new compound of the inventionexhibits affinity for both the ORL-1 receptor and the μ receptor. Inanother embodiment, a new compound of the invention acts as an ORL-1receptor agonist and as a μ receptor agonist. In another embodiment, anew compound of the invention acts as an ORL-1 receptor partial agonistand as a μ receptor agonist. In another embodiment, a new compound ofthe invention acts as an ORL-1 receptor partial agonist and as a μreceptor antagonist. In another embodiment, a new compound of theinvention acts as an ORL-1 receptor antagonist and as a μ receptoragonist.

Certain new compounds of the invention can be used to treat an animalsuffering from chronic or acute pain.

It is a further object of the invention to provide methods of treatingchronic or acute pain in an animal by administering one or moreSubstituted-Quinoxaline-Type Piperidine Compounds of the invention to ananimal in need of such treatment. In certain embodiments, such newSubstituted-Quinoxaline-Type Piperidine Compounds effectively treatchronic or acute pain in the animal, while producing fewer or reducedside effects compared to previously available compounds.

The invention encompasses compounds of Formula (I) and Formula (II):

and pharmaceutically acceptable derivatives thereof wherein:

Y₁ is O or S;

Q is selected from fused benzo or (5- or 6-membered)heteroaryl;

each R₂ is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT₃, —C(═O)T₃, —C(═O)OT₃,        —C(═O)N(T₁)(T₂), —S(═O)₂OH, —S(═O)T₃, —S(═O)₂T₃,        —S(═O)₂N(T₁)(T₂), —N(T₁)(T₂), —N(T₃)C(═O)T₃,        —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(═O)₂T₃, or —N(T₃)S(═O)₂N(T₁)(T₂);        or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₈ groups;        or    -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₇ groups;

a is an integer selected from 0, 1 or 2;

the dashed line in the 6-membered, nitrogen-containing ring that isfused to the Q group denotes the presence or absence of a bond, and whenthat dashed line denotes the presence of a bond then R₃ and one R₄ areabsent;

R₃ is selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₄)alkyl which is unsubstituted or substituted with 1,        2 or 3 groups independently selected from —OH, —(C₁-C₄)alkoxy,        —N(R₆)₂, —C(═O)OR₉, or —C(═O)N(R₆)₂; or    -   (c) —(C₃-C₇)cycloalkyl which is unsubstituted or substituted        with 1, 2 or 3 groups independently selected from —OH,        —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —N(R₆)₂, —C(═O)OR₉, or        —C(═O)N(R₆)₂;

each R₄ is independently selected from:

-   -   (a) —H; or    -   (b) -halo, —CN, or —NO₂; or    -   (c) —X, —CH₂X, —CH₂CH₂X, —(C₁-C₆)alkyl-X, -(5- or        6-membered)heterocycle-X, -(5- or        6-membered)heterocycle-(C₁-C₆)alkyl-X, or -(5- or        6-membered)heterocycle-(C₁-C₆)alkyl-R₈; or    -   (d) —C(═Y)CN, —C(═Y)X, —C(═Y)T₃, —C(═Y)YX, —C(═Y)YT₃,        —C(═Y)N(T₁)(T₂), —C(═Y)N(R₉)CN, —C(═Y)N(R₉)X,        —C(═Y)N(R₉)CH₂CH₂N(T₁)(T₂), —C(═Y)N(R₉)YH, —C(═Y)N(R₉)YX,        —C(═Y)N(R₉)YCH₂X, —C(═Y)N(R₉)YCH₂CH₂X, or —C(═Y)N(R₉)S(═O)₂T₃;        or    -   (e) —N(R₉)X, —N(R₉)—CH₂X, —N(R₉)—CH₂CH₂X, —N(R₉)—CH₂CH₂N(R₉)X,        —N(R₉)CH₂CH₂N(T₁)(T₂), —N(R₉)CH₂C(═Y)X,        —N((C₁-C₆)alkyl-C(═O)OR₉)₂, —N(R₉)CH₂N(R₉)C(═N(R₁₂))N(R₁₂)₂,        —N(R₉)—CH₂CH₂N(R₉)C(═N(R₁₂))N(R₁₂)₂, —N(T₁)(T₂), —N(T₃)C(═Y)T₃,        —N(T₃)C(═Y)YT₃, —N(T₃)C(═Y)N(T₁)(T₂), —N(T₃)S(═O)₂T₃, or        —N(T₃)S(═O)₂N(T₁)(T₂); or    -   (f) —YH, —CH₂YH, —CH₂CH₂YH, —YX, or —YT₃; or    -   (g) —S(═O)T₃, —S(═O)₂T₃, —S(═O)T₃, —S(═O)N(T₁)(T₂),        —S(═O)₂N(T₁)(T₂), —S(═O)X, or —S(═O)₂X;

X is:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₈ groups;        or    -   (b) -phenyl, -benzyl, -naphthalenyl, —(C₁₄)aryl,        —(C₁-C₆)alkyl-(5- or 6-membered)heteroaryl or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₇ groups;

each Y is independently selected from O or S;

A and B are independently selected from:

-   -   (a) —H, —CN, —C(═O)OT₃, or —C(═O)N(T)₁(T₂); or    -   (b) —(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, or —(C₁-C₆)alkoxy, each of        which is unsubstituted or substituted with 1 or 2 substituents        independently selected from —OH, —S(═O)₂NH₂, —N(R₆)₂, ═NR₆,        —C(═O)OT₃, —C(═O)N(R₆)₂, —N(R₆)C(═O)R₉, and -(5- or        6-membered)heterocycle, or 1, 2 or 3 independently selected        -halo; or    -   (c) A-B can together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7 or 8        substituents independently selected from —OH, —(C₁-C₄)alkyl,        -halo, and —C(halo)₃, and which bridge optionally contains        —HC═CH— or —O— within the (C₂-C₆)bridge; wherein the 6-membered,        nitrogen-containing ring that is fused to the Q group can be in        the endo- or exo-configuration with respect to the A-B bridge;        or    -   (d) A-B can together form a —CH₂—N(R_(a))—CH₂— bridge, a

bridge, or a

bridge;

wherein the 6-membered, nitrogen-containing ring that is fused to the Qgroup can be in the endo- or exo- configuration with respect to the A-Bbridge;

R_(a) is selected from —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—CH₂—C(═O)—R_(c), —(CH₂)—C(═O)—OR_(c), —(CH₂)—C(═O)—N(R_(c))₂,—(CH₂)₂—O—R_(c), —(CH₂)₂—S(═O)₂—N(R_(c))₂, R_(c), or—(CH₂)₂—N(R_(c))S(═O)₂—R_(c);

R_(b) is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₇)cycloalkyl,        or —N(R_(c))-(3- to 7-membered)heterocycle; or    -   (b) -phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups; or    -   (c) —N(R_(c))-phenyl, —N(R_(c))-naphthalenyl,        —N(R_(c))—(C₁₄)aryl, or —N(R_(c))-(5- to 10-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups;

each R_(c) is independently selected from —H or —(C₁-C₄)alkyl;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R₁]_(h)—, wherein h is 0or 1; [(C₂-C₁₀)alkenyl optionally substituted by R₁]—; or—(C₁-C₁₀)alkyl-NR₆C(═Y)—;

each R₁ is independently selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R₆)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV₁, or —C(═O)CN; or    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₈ groups; or    -   (c)

or

-   -   (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with an R₇ group; or

—Z—R₁ is 3,3-diphenylpropyl- optionally substituted at the 3 carbon ofthe propyl with —CN, —C(═O)N(R₆)₂, —C(═O)OV₁, or -tetrazolyl; or

—Z—R₁ is —(C₁-C₄)alkyl substituted with tetrazolyl;

each R₆ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atomcan together form a 5- to 8-membered ring, wherein the number of atomsin the ring includes the nitrogen atom, and in which one of the 5- to8-membered ring carbon atoms is optionally replaced by O, S, or N(T₃);

each R₇ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═N(R₉), —N(R₉)₂, —N(R₉)OH, —N(R₉)S(═O)R₁₂,—N(R₉)S(═O)₂R₁₂, —N(R₉)C(═O)R₁₂, —N(R₉)C(═O)N(T₁)(T₂), —N(R₉)C(═O)OR₁₂,—C(═O)R₉, —C(═O)N(T₁)(T₂), —C(═O)OR₉, —OC(═O)R₉, —OC(═O)N(T₁)(T₂),—OC(═O)OR₉, —S(═O)R₉, or —S(═O)₂R₉;

each R₈ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, -phenyl,—(C₁-C₆)alkyl-C(═O)OR₉, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo),—CN, ═O, ═S, -halo, —N₃, —NO₂, —CH═N(R₉), —NR₉(C₁-C₆)alkyl-C(═O)OR₉,—N(R₉)₂, —N(R₉)OH, —N(R₉)S(═O)R₁₂, —N(R₉)S(═O)₂R₁₂, —N(R₉)C(═O)R₁₂,—N(R₉)C(═O)N(T₁)(T₂), —N(R₉)C(═O)OR₁₂, —C(═O)R₉, —C(═O)—C(═O)OR₉,—C(═O)N(T₁)(T₂), —C(═O)OR₉, —OC(═O)R₉, —OC(═O)N(T₁)(T₂), —OC(═O)OR₉,—S(═O)R₉, or —S(═O)₂R₉;

each R₉ is independently selected from —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle,-(5- to 10-membered)heteroaryl, —C(halo)₃, —CH(halo)₂, or —CH₂(halo);

if h is 0, then R₁₁ can be selected from —H, —CN, —C(═O)OR₉, or—C(═O)N(R₆)₂ or R₁₁ can be —(C₁-C₄)alkyl which is unsubstituted orsubstituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂, —C(═O)OR₉, or—C(═O)N(R₆)₂;

if h is 1, then R₁₁ can be selected from —H, —CN, —OH, -halo, —C(═O)OR₉,or —C(═O)N(R₆)₂ or R₁₁ can be —(C₁-C₄)alkyl which is unsubstituted orsubstituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂, —C(═O)OR₉, or—C(═O)N(R₆)₂;

otherwise, where Z is —(C₁-C₁₀)alkyl-NR₆C(═Y)—, then R₁₁ can be selectedfrom —H, —CN, —C(═O)OR₉, or —C(═O)N(R₆)₂ or R₁₁ can be —(C₁-C₄)alkylwhich is unsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂,—C(═O)OR₉, or —C(═O)N(R₆)₂;

each R₁₂ is independently selected from —H or —(C₁-C₄)alkyl;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11;

e and f are each an integer independently selected from 0, 1, 2, 3, 4,or 5 provided that 2≦(e+f)≦5;

j and k are each an integer independently selected from 0, 1, 2, 3, or 4provided that 1≦(j+k)≦4;

each p is an integer independently selected from 0, 1, 2, 3, or 4;

each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2 or 3 independently selected R₈groups and, optionally, in which any —(C₁-C₁₀)alkyl carbon atom exceptthe carbon atom bonded directly to the atom to which T₁, T₂, or T₃ isattached is independently replaced by O, S, or N(R₆), or T₁ and T₂ cantogether form a 5- to 8-membered ring where the number of atoms in thering includes the nitrogen atom to which T₁ and T₂ are bonded, said 5-to 8-membered ring is unsubstituted or substituted with 1, 2 or 3independently selected R₈ groups and, optionally, any carbon atom insaid 5- to 8-membered ring is independently replaced by O, S, or N(R₆);

each V₁ is independently selected from —H, —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, -phenyl, or -benzyl; and

each halo is independently selected from —F, —Cl, —Br, or —I.

A compound of Formula (I) or Formula (II) or a pharmaceuticallyacceptable derivative thereof (a “Substituted-Quinoxaline-TypePiperidine Compound”) is useful, e.g., as an analgesic,anti-inflammatory, diuretic, anesthetic agent, neuroprotective agent,anti-hypertensive, an anxiolytic agent, an agent for appetite control,hearing regulator, anti-tussive, anti-asthmatic, modulator of locomotoractivity, modulator of learning and memory, regulator ofneurotransmitter release, regulator of hormone release, kidney functionmodulator, anti-depressant, agent to treat memory loss due toAlzheimer's disease and/or other dementias, anti-epileptic,anti-convulsant, agent to treat withdrawal from alcohol, agent to treatwithdrawal from drug(s) of addiction, agent to control water balance,agent to control sodium excretion, and/or agent to control arterialblood pressure disorder(s).

A Substituted-Quinoxaline-Type Piperidine Compound is useful fortreating and/or preventing pain, anxiety, cough, diarrhea, high bloodpressure, epilepsy, anorexia/cachexia, urinary incontinence, drug abuse,a memory disorder, obesity, constipation, depression, dementia, orParkinsonism (each being a “Condition”) in an animal.

The invention also relates to compositions comprising an effectiveamount of a Substituted-Quinoxaline-Type Piperidine Compound and apharmaceutically acceptable carrier or excipient. The compositions areuseful for treating or preventing a Condition in an animal.

The invention further relates to methods for treating a Condition,comprising administering to an animal in need thereof an effectiveamount of a Substituted-Quinoxaline-Type Piperidine Compound.

The invention further relates to methods for preventing a Condition,comprising administering to an animal in need thereof an effectiveamount of a Substituted-Quinoxaline-Type Piperidine Compound.

The invention further relates to the use of aSubstituted-Quinoxaline-Type Piperidine Compound, e.g., of Formulas (I)and/or (II), for the manufacture of a medicament useful for treating aCondition.

The invention further relates to the use of aSubstituted-Quinoxaline-Type Piperidine Compound, e.g., of Formulas (I)and/or (II), for the manufacture of a medicament useful for preventing aCondition.

The invention still further relates to methods for inhibiting ORL-1receptor function in a cell, comprising contacting a cell capable ofexpressing the ORL-1 receptor with an ORL-1 receptor function inhibitingamount of a Substituted-Quinoxaline-Type Piperidine Compound.

The invention still further relates to methods for activating ORL-1receptor function in a cell, comprising contacting a cell capable ofexpressing the ORL-1 receptor with an ORL-1 receptor function activatingamount of a Substituted-Quinoxaline-Type Piperidine Compound.

The invention still further relates to methods for preparing acomposition, comprising the step of admixing aSubstituted-Quinoxaline-Type Piperidine Compound and a pharmaceuticallyacceptable carrier or excipient.

The invention still further relates to a kit comprising a containercontaining an effective amount of a Substituted-Quinoxaline-TypePiperidine Compound.

The invention also provides novel intermediates for use in making theSubstituted-Quinoxaline-Type Piperidine Compounds.

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention. Other objects andadvantages of the invention will become apparent from the followingdetailed description thereof.

4. DETAILED DESCRIPTION OF THE INVENTION

The invention encompasses compounds of Formula (I.1) and Formula (II.1):

or a pharmaceutically acceptable derivative thereof wherein:

Y₁ is O or S;

Q is selected from fused benzo or (5- or 6-membered)heteroaryl;

each R₂ is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT₃, —C(═O)T₃, —C(═O)OT₃,        —C(═O)N(T₁)(T₂), —S(O)₃H, —S(O)T₃, —S(O)₂T₃, —S(O)₂N(T₁)(T₂),        —N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(O)₂T₃,        or —N(T₃)S(O)₂N(T₁)(T₂); or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₂)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₂-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 R₈ groups; or    -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 R₇ groups;

a is an integer from 0 to 2;

the dashed line in the fused piperazine ring denotes the presence orabsence of a bond, and when that dashed line denotes the presence of abond then R₃ and one R₄ are absent;

R₃ is independently selected from —H or —(C₁-C₄)alkyl which isunsubstituted or substituted with 1, 2, or 3 of —OH, —(C₁-C₄)alkoxy,—N(R₆)₂, —C(═O)OR₉, or —C(═O)N(R₆)₂;

each R₄ is independently selected from:

-   -   (a) —H; or    -   (b) -halo, —CN, or —NO₂; or    -   (c) —X, —CH₂X, or —CH₂CH₂X; or    -   (d) —C(Y)CN, —C(Y)X, —C(Y)T₃, —C(Y)YX, —C(Y)YT₃, —C(Y)N(T₁)(T₂),        —C(Y)N(R₉)CN, —C(Y)N(R₉)X, —C(Y)N(R₉)YH, —C(Y)N(R₉)YX,        —C(Y)N(R₉)YCH₂X, —C(Y)N(R₉)YCH₂CH₂X, or —C(Y)N(R₉)S(O)₂T₃; or

(e) —N(R₉)X, —N(R₉)—CH₂X, —N(R₉)—CH₂CH₂X,—N(R₉)CH₂N(R₉)C(═N(R₁₂))N(R₁₂)₂, —N(R₉)—CH₂CH₂N(R₉)C(═N(R₁₂))N(R₁₂)₂,—N(T₁)(T₂), —N(T₃)C(Y)T₃, —N(T₃)C(Y)YT₃, —N(T₃)C(Y)N(T₁)(T₂),—N(T₃)S(O)₂T₃, or —N(T₃)S(O)₂N(T₁)(T₂); or

-   -   (f) —YH, —CH₂YH, —CH₂CH₂YH, —YX, or —YT₃; or    -   (g) —S(O)T₃, —S(O)₂T₃, —S(O)N(T₁)(T₂), —S(O)₂N(T₁)(T₂), —S(O)X,        or —S(O)₂X;

X is:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 R₈ groups; or    -   (b) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 R₇ groups;

each Y is independently selected from O or S;

A and B are independently selected from:

-   -   (a) —H, —CN, —C(═O)OT₃, —C(═O)N(T)₁(T₂), —(C₃-C₁₂)cycloalkyl,        —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or        —(C₂-C₆)alkynyl, each of which —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl or        —(C₂-C₆)alkynyl is unsubstituted or substituted with 1 or 2        substituents selected from —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆,        —C(═O)OT₃, —C(═O)N(R₆)₂, —N(R₆)C(═O)R₉ and -(5- or        6-membered)heterocycle or from 1 to 3 independently selected        -halo; or    -   (b) A-B can together form a (C₂-C₆)bridge, which is        unsubstituted or optionally substituted with from 1 to 3 —OH or        optionally contains —HC═CH— within the (C₂-C₆)bridge; or    -   (c) A-B can together form a —CH₂—N(R_(a))—CH₂— bridge, a

bridge, or a

bridge;

R_(a) is selected from —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—CH₂—C(═O)—R_(c), —(CH₂)—C(═O)—OR_(c), —(CH₂)—C(═O)—N(R_(c))₂,—(CH₂)₂—O—R_(c), —(CH₂)₂—S(O)₂—N(R_(c))₂, R_(c), or—(CH₂)₂—N(R_(c))S(O)₂—R_(c);

R_(b) is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₇)cycloalkyl,        or —N(R_(c))-(3- to 7-membered)heterocycle; or    -   (b) -phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3 R₇        groups; or    -   (c) —N(R_(c))-phenyl, —N(R_(c))-naphthalenyl,        —N(R_(c))—(C₁₄)aryl, or —N(R_(c))-(5- to 10-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3 R₇        groups;

each R_(c) is independently selected from —H or —(C₁-C₄)alkyl;

Z is —[(C₁-C₁₀)alkyl]_(h)-, wherein h is 0 or 1; or—(C₁-C₁₀)alkyl-NR₆C(═Y)—;

R₁ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R₆)₂,        —S(O)NH₂, —S(O)₂NH₂, —C(═O)OV₁, or —C(═O)CN; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle,        each of which is unsubstituted or substituted with an R₈ group,        or

or

-   -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with an R₇ group; or

—Z—R₁ is 3,3-diphenylpropyl- optionally substituted at the 3 carbon ofthe propyl with —CN, —C(═O)N(R₆)₂, —C(═O)OV₁, or -tetrazolyl; or

—Z—R₁ is —(C₁-C₄)alkyl substituted with tetrazolyl;

each R₆ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atomcan form a 5- to 8-membered ring, the number of atoms in the ringincluding the nitrogen atom, in which one of the ring carbon atoms isoptionally replaced by O, S, or N(T₃);

each R₇ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═N(R₉), —N(R₉)₂, —N(R₉)OH, —N(R₉)S(O)R₁₂,—N(R₉)S(O)₂R₁₂, —N(R₉)C(═O)R₁₂, —N(R₉)C(═O)N(T₁)(T₂), —N(R₉)C(═O)OR₁₂,—C(═O)R₉, —C(═O)N(T₁)(T₂), —C(═O)OR₉, —OC(═O)R₉, —OC(═O)N(T₁)(T₂),—OC(═O)OR₉, —S(O)R₉, or —S(O)₂R₉;

each R₈ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O,═S, -halo, —N₃, —NO₂, —CH═N(R₉), —N(R₉)₂, —N(R₉)OH, —N(R₉)S(O)R₁₂,—N(R₉)S(O)₂R₁₂, —N(R₉)C(═O)R₁₂, —N(R₉)C(═O)N(T₁)(T₂), —N(R₉)C(═O)OR₁₂,—C(═O)R₉, —C(═O)N(T₁)(T₂), —C(═O)OR₉, —OC(═O)R₉, —OC(═O)N(T₁)(T₂),—OC(═O)OR₉, —S(O)R₉, or —S(O)₂R₉;

each R₉ is independently selected from —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂(halo);

if h is 0, R₁₁ is selected from —H, —C(═O)OR₉, or —C(═O)N(R₆)₂ or—(C₁-C₄)alkyl which is unsubstituted or substituted with —OH,—(C₁-C₄)alkoxy, —N(R₆)₂, —C(═O)OR₉, or —C(═O)N(R₆)₂;

if h is 1, R₁₁ is selected from —H, —OH, -halo, —C(═O)OR₉, or—C(═O)N(R₆)₂ or —(C₁-C₄)alkyl which is unsubstituted or substituted with—OH, —(C₁-C₄)alkoxy, —N(R₆)₂, —C(═O)OR₉, or —C(═O)N(R₆)₂;

each R₁₂ is independently selected from —H or —(C₁-C₄)alkyl;

m is an integer from 1 to 7;

e and f are independently an integer from 0 to 5 provided that 2≦(e+≦5;

j and k are independently an integer from 0 to 4 provided that1≦(j+k)≦4;

each p is independently 0 or 1;

each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2 or 3 R₈ groups and, optionally,in which any —(C₁-C₁₀)alkyl carbon atom except the carbon atom bondeddirectly to the atom to which T₁, T₂, or T₃ is attached is independentlyreplaced by O, S, or N(R₆), or T₁ and T₂ together can form a 5- to8-membered ring where the number of atoms in the ring includes thenitrogen atom to which T₁ and T₂ are bonded, said 5- to 8-membered ringis unsubstituted or substituted with 1, 2 or 3 R₈ groups and,optionally, any carbon atom in said 5- to 8-membered ring isindependently replaced by O, S, or N(R₆);

each V₁ is independently selected from —H, —(C₃-C₇)cycloalkyl, -phenyl,or -benzyl; and

each halo is independently selected from —F, —Cl, —Br, or —I.

The invention encompasses compounds of Formula (I.2) and Formula (II.2):

or a pharmaceutically acceptable derivative thereof wherein:

Y₁ is O or S;

Q is selected from fused benzo or (5- or 6-membered)heteroaryl;

each R₂ is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT₃, —C(═O)T₃, —C(═O)OT₃,        —C(═O)N(T₁)(T₂), —S(O)₃H, —S(O)T₃, —S(O)₂T₃, —S(O)₂N(T₁)(T₂),        —N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(O)₂T₃,        or —N(T₃)S(O)₂N(T₁)(T₂); or

(b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy,—(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,—(C₈-C₂₀)tricycloalkenyl, -(5- or 6-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with 1, 2 or 3 independently selected R₈ groups; or

-   -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₇ groups;

a is an integer selected from 0, 1 or 2;

the dashed line in the fused piperazine ring denotes the presence orabsence of a bond, and when that dashed line denotes the presence of abond then R₃ and one R₄ are absent;

R₃ is selected from —H, —(C₁-C₄)alkyl which is unsubstituted orsubstituted with 1, 2, or 3 of independently selected —OH,—(C₁-C₄)alkoxy, —N(R₆)₂, —C(═O)OR₉, or —C(═O)N(R₆)₂, or—(C₃-C₇)cycloalkyl which is unsubstituted or substituted with 1, 2, or 3of independently selected —OH, —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —N(R₆)₂,—C(═O)OR₉, or —C(═O)N(R₆)₂;

each R₄ is independently selected from:

-   -   (a) —H; or    -   (b) -halo, —CN, or —NO₂; or    -   (c) —X, —CH₂X, or —CH₂CH₂X; or    -   (d) —C(Y)CN, —C(Y)T₃, —C(Y)YX, —C(Y)YT₃, —C(Y)N(T₁)(T₂),        —C(Y)N(R₉)CN, —C(Y)N(R₉)X, —C(Y)N(R₉)YH, —C(Y)N(R₉)YX,        —C(Y)N(R₉)YCH₂X, —C(Y)N(R₉)YCH₂CH₂X, or —C(Y)N(R₉)S(O)₂T₃; or    -   (e) —N(R₉)X, —N(R₉)—CH₂X, —N(R₉)—CH₂CH₂X,        —N(R₉)CH₂N(R₉)C(═N(R₁₂))N(R₁₂)₂,        —N(R₉)—CH₂CH₂N(R₉)C(═N(R₁₂))N(R₁₂)₂, —N(T₁)(T₂), —N(T₃)C(Y)T₃,        —N(T₃)C(Y)YT₃, —N(T₃)C(Y)N(T₁)(T₂), —N(T₃)S(O)₂T₃, or        —N(T₃)S(O)₂N(T₁)(T₂); or    -   (f) —YH, —CH₂YH, —CH₂CH₂YH, —YX, or —YT₃; or    -   (g) —S(O)T₃, —S(O)₂T₃, —S(O)N(T₁)(T₂), —S(O)₂N(T₁)(T₂), —S(O)X,        or —S(O)₂X;

X is:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₈ groups;        or    -   (b) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₇ groups;

each Y is independently selected from O or S;

A and B are independently selected from:

-   -   (a) —H, —CN, —C(═O)OT₃, —C(═O)N(T)₁(T₂), —(C₃-C₁₂)cycloalkyl,        —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,        —(C₂-C₆)alkynyl or —(C₁-C₆)alkoxy, each of which        —(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl,        —(C₂-C₆)alkenyl or —(C₂-C₆)alkynyl is unsubstituted or        substituted with 1 or 2 substituents independently selected from        —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆, —C(═O)OT₃, —C(═O)N(R₆)₂,        —N(R₆)C(═O)R₉ and -(5- or 6-membered)heterocycle or 1, 2 or 3        independently selected -halo; or    -   (b) A-B can together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2 or 3 —OH groups, and        which bridge optionally contains —HC═CH— within the        (C₂-C₆)bridge; wherein the piperazine ring that is fused to the        Q group can be in the endo- or exo- configuration with respect        to the A-B bridge;    -   or    -   (c) A-B can together form a —CH₂—N(R_(a))—CH₂— bridge, a

bridge, or a

bridge;

wherein the piperazine ring that is fused to the Q group can be in theendo- or exo-configuration with respect to the A-B bridge;

R_(a) is selected from —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—CH₂—C(═O)—R_(c), —(CH₂)—C(═O)—OR_(c), —(CH₂)—C(═O)—N(R_(c))₂,—(CH₂)₂—O—R_(c), —(CH₂)₂—S(O)₂—N(R_(c))₂, R_(c), or—(CH₂)₂—N(ROS(O)₂—R₉;

R_(b) is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₇)cycloalkyl,        or —N(R_(c))-(3- to 7-membered)heterocycle; or    -   (b) -phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups; or    -   (c) —N(R_(c))-phenyl, —N(R_(c))-naphthalenyl,        —N(R_(c))—(C₁₄)aryl, or —N(R_(c))-(5- to 10-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups;

each R_(c) is independently selected from —H or —(C₁-C₄)alkyl;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R₁]_(h)—, wherein h is 0or 1; or —(C₁-C₁₀)alkyl-NR₆C(═Y)—;

each R₁ is independently selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R₆)₂,        —S(O)NH₂, —S(O)₂NH₂, —C(═O)OV₁, or —C(═O)CN; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₈ groups; or

or

-   -   (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with an R₇ group; or    -   —Z—R₁ is 3,3-diphenylpropyl- optionally substituted at the 3        carbon of the propyl with —CN, —C(═O)N(R₆)₂, —C(═O)OV₁, or        -tetrazolyl; or    -   —Z—R₁ is —(C₁-C₄)alkyl substituted with tetrazolyl;

each R₆ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atomcan together form a 5- to 8-membered ring, wherein the number of atomsin the ring includes the nitrogen atom, and in which one of the 5- to8-membered ring carbon atoms is optionally replaced by O, S, or N(T₃);

each R₇ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═N(R₉), —N(R₉)₂, —N(R₉)OH, —N(R₉)S(O)R₁₂,—N(R₉)S(O)₂R₁₂, —N(R₉)(C═O)R₁₂, —N(R₉)C(═O)N(T₁)(T₂), —N(R₉)C(═O)OR₁₂,—C(═O)R₉, —C(═O)N(T₁)(T₂), —C(═O)OR₉, —OC(═O)R₉, —OC(═O)N(T₁)(T₂),—OC(═O)OR₉, —S(O)R₉, or —S(O)₂R₉;

each R₈ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, (C₁-C₆)alkyl-C(═O)OR₉, —OR₉, —SR₉, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo, —N₃, —NO₂, —CH═N(R₉),—N(R₉)(C₁-C₆)alkyl-C(═O)OR₉, —N(R₉)₂, —N(R₉)OH, —N(R₉)S(O)R₁₂,—N(R₉)S(O)₂R₁₂, —N(R₉)C(═O)R₁₂, —N(R₉)C(═O)N(T₁)(T₂), —N(R₉)C(═O)OR₁₂,—C(═O)R₉, —C(═O)N(T₁)(T₂), —C(═O)OR₉, —OC(═O)R₉, —OC(═O)N(T₁)(T₂),—OC(═O)OR₉, —S(O)R₉, or —S(O)₂R₉;

each R₉ is independently selected from —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂(halo);

if h is 0, then R₁₁ can be selected from —H, —C(═O)OR₉, or —C(═O)N(R₆)₂or R_(u) can be —(C₁-C₄)alkyl which is unsubstituted or substituted with—OH, —(C₁-C₄)alkoxy, —N(R₆)₂, —C(═O)OR₉, or —C(═O)N(R₆)₂;

if h is 1, then R₁₁ can be selected from —H, —OH, -halo, —C(═O)OR₉, or—C(═O)N(R₆)₂ or R₁₁ can be —(C₁-C₄)alkyl which is unsubstituted orsubstituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂, —C(═O)OR₉, or—C(═O)N(R₆)₂;

otherwise, where Z is —(C₁-C₁₀)alkyl-NR₆C(═Y)—, then R₁₁ can be selectedfrom —H, —C(═O)OR₉, or —C(═O)N(R₆)₂ or R₁₁ can be —(C₁-C₄)alkyl which isunsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂,—C(═O)OR₉, or —C(═O)N(R₆)₂;

each R₁₂ is independently selected from —H or —(C₁-C₄)alkyl;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6 or 7;

e and f are each an integer independently selected from 0, 1, 2, 3, 4 or5 provided that 2≦(e+f)≦5;

j and k are each an integer independently selected from 0, 1, 2, 3 or 4provided that 1≦(j+k)≦4;

each p is an integer independently selected from 0 or 1;

each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2 or 3 independently selected R₈groups and, optionally, in which any —(C₁-C₁₀)alkyl carbon atom exceptthe carbon atom bonded directly to the atom to which T₁, T₂, or T₃ isattached is independently replaced by O, S, or N(R₆), or T₁ and T₂ cantogether form a 5- to 8-membered ring where the number of atoms in thering includes the nitrogen atom to which T₁ and T₂ are bonded, said 5-to 8-membered ring is unsubstituted or substituted with 1, 2 or 3independently selected R₈ groups and, optionally, any carbon atom insaid 5- to 8-membered ring is independently replaced by O, S, or N(R₆);

each V₁ is independently selected from —H, —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, -phenyl, or -benzyl; and

each halo is independently selected from —F, —Cl, —Br, or —I.

The invention encompasses compounds of Formula (I.3) and Formula (II.3):

or a pharmaceutically acceptable derivative thereof wherein:

Y₁ is O or S;

Q is selected from fused benzo or (5- or 6-membered)heteroaryl;

each R₂ is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT₃, —C(═O)T₃, —C(═O)OT₃,        —C(═O)N(T₁)(T₂), —S(O)₃H, —S(O)T₃, —S(O)₂T₃, —S(O)₂N(T₁)(T₂),        —N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(O)₂T₃,        or —N(T₃)S(O)₂N(T₁)(T₂); or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₈ groups;        or    -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₇ groups;

a is an integer selected from 0, 1 or 2;

the dashed line in the fused piperazine ring denotes the presence orabsence of a bond, and when that dashed line denotes the presence of abond then R₃ and one R₄ are absent;

R₃ is selected from —H, —(C₁-C₄)alkyl which is unsubstituted orsubstituted with 1, 2, or 3 of independently selected —OH,—(C₁-C₄)alkoxy, —N(R₆)₂, —C(═O)OR₉, or —C(═O)N(R₆)₂, or—(C₃-C₇)cycloalkyl which is unsubstituted or substituted with 1, 2, or 3of independently selected —OH, —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —N(R₆)₂,—C(═O)OR₉, or —C(═O)N(R₆)₂;

each R₄ is independently selected from:

-   -   (a) —H; or    -   (b) -halo, —CN, or —NO₂; or    -   (c) —X, —CH₂X, or —CH₂CH₂X; or    -   (d) —C(Y)CN, —C(Y)X, —C(Y)T₃, —C(Y)YX, —C(Y)YT₃, —C(Y)N(T₁)(T₂),        —C(Y)N(R₉)CN, —C(Y)N(R₉)X, —C(Y)N(R₉)YH, —C(Y)N(R₉)YX,        —C(Y)N(R₉)YCH₂X, —C(Y)N(R₉)YCH₂CH₂X, or —C(Y)N(R₉)S(O)₂T₃; or    -   (e) —N(R₉)X, —N(R₉)—CH₂X, —N(R₉)—CH₂CH₂X,        —N(R₉)CH₂N(R₉)C(═N(R₁₂))N(R₁₂)₂,        —N(R₉)—CH₂CH₂N(R₉)C(═N(R₁₂))N(R₁₂)₂, —N(T₁)(T₂), —N(T₃)C(Y)T₃,        —N(T₃)C(Y)YT₃, —N(T₃)C(Y)N(T₁)(T₂), —N(T₃)S(O)₂T₃, or        —N(T₃)S(O)₂N(T₁)(T₂); or    -   (f) —CH₂YH, —CH₂CH₂YH, —YX, or —YT₃; or    -   (g) —S(O)T₃, —S(O)₂T₃, —S(O)N(T₁)(T₂), —S(O)₂N(T₁)(T₂), —S(O)X,        or —S(O)₂X;

X is:

-   -   (a) —H, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy,        —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₈ groups;        or    -   (b) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₇ groups;

each Y is independently selected from O or S;

A and B are independently selected from:

-   -   (a) —H, —CN, —C(═O)OT₃, —C(═O)N(T) (T₂), —(C₃-C₁₂)cycloalkyl,        —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,        —(C₂-C₆)alkynyl or —(C₁-C₆)alkoxy, each of which        —(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl,        —(C₂-C₆)alkenyl or —(C₂-C₆)alkynyl is unsubstituted or        substituted with 1 or 2 substituents independently selected from        —OH, —S(O)₂NH₂, —N(R₆)₂, ═NR₆, —C(═O)OT₃, —C(═O)N(R₆)₂,        —N(R₆)C(═O)R₉ and -(5- or 6-membered)heterocycle or 1, 2 or 3        independently selected -halo; or    -   (b) A-B can together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2 or 3 —OH groups, and        which bridge optionally contains —HC═CH— or —O— within the        (C₂-C₆)bridge; wherein the piperazine ring that is fused to the        Q group can be in the endo- or exo- configuration with respect        to the A-B bridge;    -   or    -   (c) A-B can together form a —CH₂—N(R_(a))—CH₂— bridge, a

bridge, or a

bridge;

wherein the piperazine ring that is fused to the Q group can be in theendo- or exo-configuration with respect to the A-B bridge;

R_(a) is selected from —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—CH₂—C(═O)—R_(c), —(CH₂)—C(═O)—OR_(c), —(CH₂)—C(═O)—N(R_(c))₂,—(CH₂)₂—O—R_(c), —(CH₂)₂—S(O)₂—N(R_(c))₂, R_(c), or—(CH₂)₂N(R_(c))S(O)₂—R_(c);

R_(b) is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₇)cycloalkyl,        or —N(R_(c))-(3- to 7-membered)heterocycle; or    -   (b) -phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups; or    -   (c) —N(R_(c))-phenyl, —N(R_(c))-naphthalenyl,        —N(R_(c))—(C₁₄)aryl, or —N(R_(c))-(5- to 10-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups;

each R_(c) is independently selected from —H or —(C₁-C₄)alkyl;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R₁]_(h)—, wherein h is 0or 1; or —(C₁-C₁₀)alkyl-NR₆C(═Y)—;

each R₁ is independently selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R₆)₂,        —S(O)NH₂, —S(O)₂NH₂, —C(═O)OV₁, or —C(═O)CN; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₈ groups; or

or

-   -   (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with an R₇ group; or    -   —Z—R₁ is 3,3-diphenylpropyl- optionally substituted at the 3        carbon of the propyl with —CN, —C(═O)N(R₆)₂, —C(═O)OV₁, or        -tetrazolyl; or    -   —Z—R₁ is —(C₁-C₄)alkyl substituted with tetrazolyl;

each R₆ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atomcan together form a 5- to 8-membered ring, wherein the number of atomsin the ring includes the nitrogen atom, and in which one of the 5- to8-membered ring carbon atoms is optionally replaced by O, S, or N(T₃);

each R₇ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═N(R₉), —N(R₉)₂, —N(R₉)OH, —N(R₉)S(O)R₁₂,—N(R₉)S(O)₂R₁₂, —N(R₉)C(═O)R₁₂, —N(R₉)C(═O)N(T₁)(T₂), —N(R₉)C(═O)OR₁₂,—C(═O)R₉, —C(═O)N(T₁)(T₂), —C(═O)OR₉, —OC(═O)R₉, —OC(═O)N(T₁)(T₂),—OC(═O)OR₉, —S(O)R₉, or —S(O)₂R₉;

each R₈ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, (C₁-C₆)alkyl-C(═O)OR₉, —OR₉, —SR₉, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —CN, ═O, —S, -halo, —N₃, —NO₂, —CH═N(R₉),—N(R₉)(C₁-C₆)alkyl-C(═O)OR₉, —N(R₉)₂, —N(R₉)OH, —N(R₉)S(O)R₁₂,—N(R₉)S(O)₂R₁₂, —N(R₉)C(═O)R₁₂, —N(R₉)C(═O)N(T₁)(T₂), —N(R₉)C(═O)OR₁₂,—C(═O)R₉, —C(═O)N(T₁)(T₂), —C(═O)OR₉, —OC(═O)R₉, —OC(═O)N(T₁)(T₂),—OC(═O)OR₉, —S(O)R₉, or —S(O)₂R₉;

each R₉ is independently selected from —H, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,-benzyl, -(3- to 6-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or—CH₂(halo);

if h is 0, then R₁₁ can be selected from —H, —C(═O)OR₉, or —C(═O)N(R₆)₂or R₁₁ can be —(C₁-C₄)alkyl which is unsubstituted or substituted with—OH, —(C₁-C₄)alkoxy, —N(R₆)₂, —C(═O)OR₉, or —C(═O)N(R₆)₂;

if h is 1, then R₁₁ can be selected from —H, —OH, -halo, —C(═O)OR₉, or—C(═O)N(R₆)₂ or R₁₁ can be —(C₁-C₄)alkyl which is unsubstituted orsubstituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂, —C(═O)OR₉, or—C(═O)N(R₆)₂;

otherwise, where Z is —(C₁-C₁₀)alkyl-NR₆C(═Y)—, then R₁₁ can be selectedfrom —H, —C(═O)OR₉, or —C(═O)N(R₆)₂ or R₁₁ can be —(C₁-C₄)alkyl which isunsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂,—C(═O)OR₉, or —C(═O)N(R₆)₂;

each R₁₂ is independently selected from —H or —(C₁-C₄)alkyl;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6 or 7;

e and f are each an integer independently selected from 0, 1, 2, 3, 4 or5 provided that 2≦(e+f)≦5;

j and k are each an integer independently selected from 0, 1, 2, 3 or 4provided that 1≦(j+k)≦4;

each p is an integer independently selected from 0 or 1;

each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2 or 3 independently selected R₈groups and, optionally, in which any —(C₁-C₁₀)alkyl carbon atom exceptthe carbon atom bonded directly to the atom to which T₁, T₂, or T₃ isattached is independently replaced by O, S, or N(R₆), or T₁ and T₂ cantogether form a 5- to 8-membered ring where the number of atoms in thering includes the nitrogen atom to which T₁ and T₂ are bonded, said 5-to 8-membered ring is unsubstituted or substituted with 1, 2 or 3independently selected R₈ groups and, optionally, any carbon atom insaid 5- to 8-membered ring is independently replaced by O, S, or N(R₆);

each V₁ is independently selected from —H, —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, -phenyl, or -benzyl; and

each halo is independently selected from —F, —Cl, —Br, or —I.

The invention encompasses compounds of Formula (I.4) and Formula (II.4):

or a pharmaceutically acceptable derivative thereof wherein:

Y₁ is O or S;

Q is selected from fused benzo or (5- or 6-membered)heteroaryl;

each R₂ is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT₃, —C(═O)T₃, —C(═O)OT₃,        —C(═O)N(T₁)(T₂), —S(═O)₂OH, —S(═O)T₃, —S(═O)₂T₃,        —S(═O)₂N(T₁)(T₂), —N(T₁)(T₂), —N(T₃)C(═O)T₃,        —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(═O)₂T₃, or —N(T₃)S(═O)₂N(T₁)(T₂);        or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₈ groups;        or    -   (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₇ groups;

a is an integer selected from 0, 1 or 2;

the dashed line in the 6-membered, nitrogen-containing ring that isfused to the Q group denotes the presence or absence of a bond, and whenthat dashed line denotes the presence of a bond then R₃ and one R₄ areabsent;

R₃ is selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₄)alkyl which is unsubstituted or substituted with 1,        2 or 3 groups independently selected from —OH, —(C₁-C₄)alkoxy,        —N(R₆)₂, —C(═O)OR₉, or —C(═O)N(R₆)₂; or    -   (c) —(C₃-C₇)cycloalkyl which is unsubstituted or substituted        with 1, 2 or 3 groups independently selected from —OH,        —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —N(R₆)₂, —C(═O)OR₉, or        —C(═O)N(R₆)₂;

each R₄ is independently selected from:

-   -   (a) —H; or    -   (b) -halo, —CN, or —NO₂; or    -   (c) —X, —(C₁-C₆)alkyl-X, -(5- or 6-membered)heterocycle-X, or        -(5- or 6-membered)heterocycle-(C₁-C₆)alkyl-X; or    -   (d) —C(═Y)CN, —C(═Y)X, —C(═Y)T₃, —C(═Y)YX, —C(═Y)YT₃,        —C(═Y)N(T₁)(T₂), —C(═Y)N(R₉)CN, —C(═Y)N(R₉)X, —C(═Y)N(R₉)YH,        —C(═Y)N(R₉)YX, —C(═Y)N(R₉)YCH₂X, —C(═Y)N(R₉)YCH₂CH₂X, or        —C(═Y)N(R₉)S(═O)₂T₃; or    -   (e) —N(R₉)X, —N(R₉)—CH₂X, —N(R₉)—CH₂CH₂X,        —N(R₉)CH₂N(R₉)C(═N(R₁₂))N(R₁₂)₂,        —N(R₉)—CH₂CH₂N(R₉)C(═N(R₁₂))N(R₁₂)₂, —N(T₁)(T₂), —N(T₃)C(═Y)T₃,        —N(T₃)C(═Y)YT₃, —N(T₃)C(═Y)N(T₁)(T₂), —N(T₃)S(═O)₂T₃, or        —N(T₃)S(═O)₂N(T₁)(T₂); or    -   (f) —YH, —CH₂YH, —CH₂CH₂YH, —YX, or —YT₃; or    -   (g) —S(═O)T₃, —S(═O)₂T₃, —S(═O)N(T₁)(T₂), —S(═O)₂N(T₁)(T₂),        —S(═O)X, or —S(═O)₂X;

X is:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalicyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or        6-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with 1, 2 or 3 independently selected R₈ groups;        or    -   (b) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or        6-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2 or 3 independently selected R₇ groups;

each Y is independently selected from O or S;

A and B are independently selected from:

-   -   (a) —H, —CN, —C(═O)OT₃, or —C(═O)N(T)₁(T₂); or    -   (b) —(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, or —(C₁-C₆)alkoxy, each of        which is unsubstituted or substituted with 1 or 2 substituents        independently selected from —OH, —S(═O)₂NH₂, —N(R₆)₂, ═NR₆,        —C(═O)OT₃, —C(═O)N(R₆)₂, —N(R₆)C(═O)R₉, and -(5- or        6-membered)heterocycle, or 1, 2 or 3 independently selected        -halo; or    -   (c) A-B can together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7 or 8        substituents independently selected from —OH, —(C₁-C₄)alkyl,        -halo, and —C(halo)₃, and which bridge optionally contains        —HC═CH— or —O— within the (C₂-C₆)bridge; wherein the 6-membered,        nitrogen-containing ring that is fused to the Q group can be in        the endo- or exo-configuration with respect to the A-B bridge;        or    -   (d) A-B can together form a —CH₂—N(R_(a))—CH₂— bridge, a

bridge, or a

bridge;

wherein the 6-membered, nitrogen-containing ring that is fused to the Qgroup can be in the endo- or exo- configuration with respect to the A-Bbridge;

R_(a) is selected from —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—CH₂—C(═O)—R_(c), —(CH₂)—C(═O)—OR_(c), —(CH₂)—C(═O)—N(R_(c))₂,—(CH₂)₂—O—R_(c), —(CH₂)₂—S(═O)₂—N(R_(c))₂, R_(c), or—(CH₂)₂—N(R_(c))S(O)₂—R_(c);

R_(b) is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₇)cycloalkyl,        or —N(R_(c))-(3- to 7-membered)heterocycle; or    -   (b) -phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups; or    -   (c) —N(R_(c))-phenyl, —N(R_(c))-naphthalenyl,        —N(R_(c))—(C₁₄)aryl, or —N(R_(c))-(5- to 10-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₇ groups;

each R_(c) is independently selected from —H or —(C₁-C₄)alkyl;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R₁]_(h)—, wherein h is 0or 1; or —(C₁-C₁₀)alkyl-NR₆C(═Y)—;

each R₁ is independently selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R₆)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV₁, or —C(═O)CN; or    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle,        each of which is unsubstituted or substituted with 1, 2 or 3        independently selected R₈ groups; or    -   (c)

or

-   -   (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with an R₇ group; or

—Z—R₁ is 3,3-diphenylpropyl- optionally substituted at the 3 carbon ofthe propyl with —CN, —C(═O)N(R₆)₂, —C(═O)OV₁, or -tetrazolyl; or

—Z—R₁ is —(C₁-C₄)alkyl substituted with tetrazolyl;

each R₆ is independently selected from —H, —(C₁-C₆)alkyl, or—(C₃-C₇)cycloalkyl, or two R₆ groups attached to the same nitrogen atomcan together form a 5- to 8-membered ring, wherein the number of atomsin the ring includes the nitrogen atom, and in which one of the 5- to8-membered ring carbon atoms is optionally replaced by O, S, or N(T₃);

each R₇ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═N(R₉), —N(R₉)₂, —N(R₉)OH, —N(R₉)S(═O)R₁₂,—N(R₉)S(═O)₂R₁₂, —N(R₉)C(═O)R₁₂, —N(R₉)C(═O)N(T₁)(T₂), —N(R₉)C(═O)OR₁₂,—C(═O)R₉, —C(═O)N(T₁)(T₂), —C(═O)OR₉, —OC(═O)R₉, —OC(═O)N(T₁)(T₂),—OC(═O)OR₉, —S(═O)R₉, or —S(═O)₂R₉;

each R₈ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR₉,—OR₉, —SR₉, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo, —N₃,—NO₂, —CH═N(R₉), —N(R₉)(C₁-C₆)alkyl-C(═O)OR₉, —N(R₉)₂, —N(R₉)OH,—N(R₉)S(═O)R₁₂, —N(R₉)S(═O)₂R₁₂, —N(R₉)C(═O)R₁₂, —N(R₉)C(═O)N(T₁)(T₂),—N(R₉)C(═O)OR₁₂, —C(═O)R₉, —C(═O)N(T₁)(T₂), —C(═O)OR₉, —OC(═O)R₉,—OC(═O)N(T₁)(T₂), —OC(═O)OR₉, —S(═O)R₉, or —S(═O)₂R₉;

each R₉ is independently selected from —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂(halo);

if h is 0, then R₁₁ can be selected from —H, —CN, —C(═O)OR₉, or—C(═O)N(R₆)₂ or R₁₁ can be —(C₁-C₄)alkyl which is unsubstituted orsubstituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂, —C(═O)OR₉, or—C(═O)N(R₆)₂;

if h is 1, then R₁₁ can be selected from —H, —CN, —OH, -halo, —C(═O)OR₉,or —C(═O)N(R₆)₂ or R₁₁ can be —(C₁-C₄)alkyl which is unsubstituted orsubstituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂, —C(═O)OR₉, or—C(═O)N(R₆)₂;

otherwise, where Z is —(C₁-C₁₀)alkyl-NR₆C(═Y)—, then R₁₁ can be selectedfrom —H, —CN, —C(═O)OR₉, or —C(═O)N(R₆)₂ or R₁₁ can be —(C₁-C₄)alkylwhich is unsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂,—C(═O)OR₉, or —C(═O)N(R₆)₂;

each R₁₂ is independently selected from —H or —(C₁-C₄)alkyl;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11;

e and f are each an integer independently selected from 0, 1, 2, 3, 4,or 5 provided that 2≦(e+f)≦5;

j and k are each an integer independently selected from 0, 1, 2, 3, or 4provided that 1≦(j+k)≦4;

each p is an integer independently selected from 0 or 1;

each T₁, T₂, and T₃ is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2 or 3 independently selected R₈groups and, optionally, in which any —(C₁-C₁₀)alkyl carbon atom exceptthe carbon atom bonded directly to the atom to which T₁, T₂, or T₃ isattached is independently replaced by O, S, or N(R₆), or T₁ and T₂ cantogether form a 5- to 8-membered ring where the number of atoms in thering includes the nitrogen atom to which T₁ and T₂ are bonded, said 5-to 8-membered ring is unsubstituted or substituted with 1, 2 or 3independently selected R₈ groups and, optionally, any carbon atom insaid 5- to 8-membered ring is independently replaced by O, S, or N(R₆);

each V₁ is independently selected from —H, —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, -phenyl, or -benzyl; and

each halo is independently selected from —F, —Cl, —Br, or —I.

4.1 Substituted-Quinoxaline-Type Piperidine Compounds of Formula (I)

As stated above, the invention encompasses Substituted-Quinoxaline-TypePiperidine Compounds of Formula (I):

or a pharmaceutically acceptable derivative thereof where R₁, R₂, R₃,R₄, Q, Y₁, Z, A, B, and a are defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds.

In one embodiment, Y₁ is O.

In another embodiment, Y₁ is S.

In another embodiment, A is H.

In another embodiment, B is H.

In another embodiment, a is 0 or 1.

In another embodiment, a is 0.

In another embodiment, a is 1.

In another embodiment, a is 2.

In another embodiment, h is 0.

In another embodiment, h is 1.

In another embodiment, h is 1 and Z is a (C₁-C₃)alkyl.

In another embodiment, h is 1, Z is a (C₁-C₃)alkyl, R₁ is phenyl, the(C₁-C₃)alkyl is substituted by another R₁, and the other R₁ is phenyl.

In another embodiment, R₁ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy,—(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₇—C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle, each ofwhich is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups.

In another embodiment, R₁ is optionally substituted cyclooctyl.

In another embodiment, R₁ is optionally substituted cyclooctenyl.

In another embodiment, R₁ is optionally substituted anthryl.

In another embodiment, h is 0 and R₁ is optionally substitutedcyclooctyl.

In another embodiment, h is 0 and R₁ is optionally substitutedcyclooctenyl.

In another embodiment, h is 0 and R₁ is optionally substituted anthryl.

In another embodiment, Y₁ is O, A and B are each H, and a is 0 or 1.

In another embodiment, Y₁ is S, A and B are each H, and a is 0 or 1.

In another embodiment, Y₁ is O, A and B are each H, and a is 0.

In another embodiment, Y₁ is S, A and B are each H, and a is 0.

In another embodiment, Y₁ is O, A and B are each H, and a is 1.

In another embodiment, Y₁ is S, A and B are each H, and a is 1.

In another embodiment, R₃ is —H, —(C₁-C₄)alkyl, or —(C₃-C₇)cycloalkyl.

In another embodiment, R₃ is —H.

In another embodiment, R₃ is —(C₁-C₄)alkyl.

In another embodiment, R₃ is methyl, ethyl, n-propyl or iso-propyl, eachoptionally substituted with one —OH, —(C₁-C₄)alkoxy, —N(R₆)₂, —C(═O)OR₉,or —C(═O)N(R₆)₂ group.

In another embodiment, R₃ is —(C₃-C₇)cycloalkyl.

In another embodiment, R₃ is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, or cycloheptyl, each optionally substituted with 1 or 2 —CH₃groups.

In another embodiment, R₃ is cyclopentyl, cyclohexyl, or cycloheptyl,each optionally substituted with one —OH, —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy,—N(R₆)₂, —C(═O)OR₉, or —C(═O)N(R₆)₂ group.

In another embodiment, R₁₁ is not —COOH.

In another embodiment, Y₁ is O, A and B are each H, R₃ is —H,—(C₁-C₄)alkyl, or —(C₃-C₇)cycloalkyl, and a is 0 or 1.

In another embodiment, Y₁ is S, A and B are each H, R₃ is —H,—(C₁-C₄)alkyl, or —(C₃-C₇)cycloalkyl, and a is 0 or 1.

In another embodiment, Y₁ is O, A and B are each H, R₃ is —H,—(C₁-C₄)alkyl, or —(C₃-C₇)cycloalkyl, and a is 0.

In another embodiment, Y₁ is S, A and B are each H, R₃ is —H,—(C₁-C₄)alkyl, or —(C₃-C₇)cycloalkyl, and a is 0.

In another embodiment, Y₁ is O, A and B are each H, R₃ is —H,—(C₁-C₄)alkyl, or —(C₃-C₇)cycloalkyl, and a is 1.

In another embodiment, Y₁ is S, A and B are each H, R₃ is —H,—(C₁-C₄)alkyl, or —(C₃-C₇)cycloalkyl, and a is 1.

In another embodiment, each R₂ is independently selected from -halo,—OH, —NH₂, —CN, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or6-membered)heterocycle, -phenyl, -naphthalenyl or -(5- or6-membered)heteroaryl.

In another embodiment, a is 2 and each R₂ is independently selected from-halo, —OH, —NH₂, —CN, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or6-membered)heterocycle, -phenyl, -naphthalenyl or -(5- or6-membered)heteroaryl.

In another embodiment, a is 1 and R₂ is selected from -halo, —OH, —NH₂,—CN, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or 6-membered)heterocycle,-phenyl, -naphthalenyl or -(5- or 6-membered)heteroaryl.

In another embodiment, a is 2 and each R₂ is independently selected from-halo, —OH, —NH₂, —CN, methyl, ethyl, n-propyl, iso-propyl, cyclopentyl,cyclohexyl, cycloheptyl, or phenyl.

In another embodiment, a is 1 and R₂ is selected from -halo, —OH, —NH₂,—CN, methyl, ethyl, n-propyl, iso-propyl, cyclopentyl, cyclohexyl,cycloheptyl, or phenyl.

In another embodiment, Q is selected from benzo, pyridino, pyrimidino,pyrazino, pyridazino, pyrrolino, imidazolino, pyrazolino, triazolino,furano, oxazolino, isoxazolino, oxadiazolino, thiopheno, thiazolino,isothiazolino, or thiadiazolino.

In another embodiment, Q is selected from benzo or pyridino.

In another embodiment, Q is benzo.

In another embodiment, Q is pyridino.

In another embodiment, Q is pyridino and the 2- and 3-positions of thepyridino are fused to the 6-membered, nitrogen-containing ring.

In another embodiment, each Y is O.

In another embodiment, each Y is S.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IA):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (I).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IB):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (I).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IC):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (I).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (ID):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (I).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (ID1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula (ID)wherein the 6-membered, nitrogen-containing ring that is fused to thebenzo is in the endo- configuration with respect to the (—CH₂—CH₂—)bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (ID2):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula (ID)wherein the 6-membered, nitrogen-containing ring that is fused to thebenzo is in the exo- configuration with respect to the (—CH₂—CH₂—)bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IE):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (I).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IE1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula (IE)wherein the 6-membered, nitrogen-containing ring that is fused to thebenzo is in the endo- configuration with respect to the (—CH₂—CH₂—CH₂—)bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IE2):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula (IE)wherein the 6-membered, nitrogen-containing ring that is fused to thebenzo is in the exo- configuration with respect to the (—CH₂—CH₂—CH₂—)bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IF):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (I).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IF1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula (IF)wherein the 6-membered, nitrogen-containing ring that is fused to thepyridino is in the endo- configuration with respect to the (—CH₂—CH₂—)bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IF2):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula (IF)wherein the 6-membered, nitrogen-containing ring that is fused to thepyridino is in the exo- configuration with respect to the (—CH₂—CH₂—)bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IG):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (I).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IG1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula (IG)wherein the 6-membered, nitrogen-containing ring that is fused to thepyridino is in the endo- configuration with respect to the(—CH₂—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IG2):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula (IG)wherein the 6-membered, nitrogen-containing ring that is fused to thepyridino is in the exo- configuration with respect to the(—CH₂—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IH):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (I).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IH1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula (IH)wherein the 6-membered, nitrogen-containing ring that is fused to thepyridino is in the endo- configuration with respect to the (—CH₂—CH₂—)bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IH2):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula (IH)wherein the 6-membered, nitrogen-containing ring that is fused to thepyridino is in the exo- configuration with respect to the (—CH₂—CH₂—)bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IJ):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (I).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IJ1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula (IJ)wherein the 6-membered, nitrogen-containing ring that is fused to thepyridino is in the endo- configuration with respect to the(—CH₂—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IJ2):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula (IJ)wherein the 6-membered, nitrogen-containing ring that is fused to thepyridino is in the exo- configuration with respect to the(—CH₂—CH₂—CH₂—) bridge.

4.2 Substituted-Quinoxaline-Type Piperidine Compounds of Formula (II)

As stated above, the invention encompasses Substituted-Quinoxaline-TypePiperidine Compounds of Formula (II):

or a pharmaceutically acceptable derivative thereof where R₁, R₂, R₃,R₄, Q, Y₁, Z, A, B, a, and the dashed line are defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds.

In one embodiment, the dashed line (representing a bond) in the6-membered, nitrogen-containing ring that is fused to the Q group isabsent and R₃ is present.

In another embodiment, the dashed line (representing one bond of adouble bond) in the 6-membered, nitrogen-containing ring that is fusedto the Q group is present, and R₃ and one R₄ are absent.

In another embodiment, Y₁ is O.

In another embodiment, Y₁ is S.

In another embodiment, A is H.

In another embodiment, B is H.

In another embodiment, a is 0 or 1.

In another embodiment, a is 0.

In another embodiment, a is 1.

In another embodiment, a is 2.

In another embodiment, h is 0.

In another embodiment, h is 1.

In another embodiment, h is 1 and Z is a (C₁-C₃)alkyl.

In another embodiment, h is 1, Z is a (C₁-C₃)alkyl, R₁ is phenyl, the(C₁-C₃)alkyl is substituted by another R₁, and the other R₁ is phenyl.

In another embodiment, R₁ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy,—(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle, each ofwhich is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups.

In another embodiment, h is 1 and Z is a (C₂-C₁₀)alkenyl.

In another embodiment, h is 1 and Z is a (C₂-C₆)alkenyl.

In another embodiment, h is 1 and Z is a propenyl.

In another embodiment h is 1, Z is propenyl and R₁ is an optionallysubstituted —(C₆-C₁₄)bicycloalkyl or —(C₈-C₂₀)tricycloalkyl.

In another embodiment h is 1, and Z—R1 is

In another embodiment, R₁ is optionally substituted cyclooctyl.

In another embodiment, R₁ is optionally substituted cyclooctenyl.

In another embodiment, R₁ is optionally substituted anthryl.

In another embodiment, h is 0 and R₁ is optionally substitutedcyclooctyl.

In another embodiment, h is 0 and R₁ is optionally substitutedcycloundecyl.

In another embodiment, h is 0 and R₁ is optionally substitutedcyclooctenyl.

In another embodiment, h is 0 and R₁ is optionally substituted anthryl.

In another embodiment, h is 0 and R₁ is optionally substituted—(C₆-C₁₄)bicycloalkyl.

In another embodiment, h is 0 and R₁ is optionally substitutedbicyclo[3.3.1]nonyl.

In another embodiment, h is 0 and R₁ is optionally substitutedbicyclo[2.2.1]hepyl.

In another embodiment, h is 0 and R₁ is optionally substituted—(C₈-C₂₀)tricycloalkyl.

In another embodiment, h is 0 and R₁ is optionally substitutedadamantyl.

In another embodiment, h is 0 and R₁ is optionally substitutednoradamantyl.

In another embodiment, if Z is —[(C₁-C₁₀)alkyl optionally substituted byR₁]_(h)— and h is 0 then R₄ is not COOH.

In another embodiment, Y₁ is O, A and B are each H, and a is 0 or 1.

In another embodiment, Y₁ is S, A and B are each H, and a is 0 or 1.

In another embodiment, Y₁ is O, A and B are each H, and a is 0.

In another embodiment, Y₁ is S, A and B are each H, and a is 0.

In another embodiment, Y₁ is O, A and B are each H, and a is 1.

In another embodiment, Y₁ is S, A and B are each H, and a is 1.

In another embodiment, the double bond in the 6-membered,nitrogen-containing ring that is fused to the Q group is present and R₃is absent.

In another embodiment, R₃ is —H, —(C₁-C₄)alkyl, or —(C₃-C₇)cycloalkyl.

In another embodiment, R₃ is —H.

In another embodiment, R₃ is —(C₁-C₄)alkyl.

In another embodiment, R₃ is methyl, ethyl, n-propyl or iso-propyl, eachoptionally substituted with one —OH, —(C₁-C₄)alkoxy, —N(R₆)₂, —C(═O)OR₉,or —C(═O)N(R₆)₂ group.

In another embodiment, R₃ is —(C₃-C₇)cycloalkyl.

In another embodiment, R₃ is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, or cycloheptyl, each optionally substituted with 1 or 2 —CH₃groups.

In another embodiment, R₃ is cyclopentyl, cyclohexyl, or cycloheptyl,each optionally substituted with one —OH, —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy,—N(R₆)₂, —C(═O)OR₉, or —C(═O)N(R₆)₂ group.

In another embodiment, R₁₁ is not —COOH.

In another embodiment, Y₁ is O, A and B are each H, the double bond inthe 6-membered, nitrogen-containing ring that is fused to the Q group ispresent, R₃ is absent, and a is 0 or 1.

In another embodiment, Y₁ is S, A and B are each H, the double bond inthe 6-membered, nitrogen-containing ring that is fused to the Q group ispresent, R₃ is absent, and a is 0 or 1.

In another embodiment, Y₁ is O, A and B are each H, the double bond inthe 6-membered, nitrogen-containing ring that is fused to the Q group ispresent, R₃ is absent, and a is 0.

In another embodiment, Y₁ is S, A and B are each H, the double bond inthe 6-membered, nitrogen-containing ring that is fused to the Q group ispresent, R₃ is absent, and a is 0.

In another embodiment, Y₁ is O, A and B are each H, the double bond inthe 6-membered, nitrogen-containing ring that is fused to the Q group ispresent, R₃ is absent, and a is 1.

In another embodiment, Y₁ is S, A and B are each H, the double bond inthe 6-membered, nitrogen-containing ring that is fused to the Q group ispresent, R₃ is absent, and a is 1.

In another embodiment, Y₁ is O, A and B are each H, R₃ is —H,—(C₁-C₄)alkyl, or —(C₃-C₇)cycloalkyl, and a is 0 or 1.

In another embodiment, Y₁ is S, A and B are each H, R₃ is —H,—(C₁-C₄)alkyl, or —(C₃-C₇)cycloalkyl, and a is 0 or 1.

In another embodiment, Y₁ is O, A and B are each H, R₃ is —H,—(C₁-C₄)alkyl, or —(C₃-C₇)cycloalkyl, and a is 0.

In another embodiment, Y₁ is S, A and B are each H, R₃ is —H,—(C₁-C₄)alkyl, or —(C₃-C₇)cycloalkyl, and a is 0.

In another embodiment, Y₁ is O, A and B are each H, R₃ is —H,—(C₁-C₄)alkyl, or —(C₃-C₇)cycloalkyl, and a is 1.

In another embodiment, Y₁ is S, A and B are each H, R₃ is —H,—(C₁-C₄)alkyl, or —(C₃-C₇)cycloalkyl, and a is 1.

In another embodiment, each R₂ is independently selected from -halo,—OH, —NH₂, —CN, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or6-membered)heterocycle, -phenyl, -naphthalenyl or -(5- or6-membered)heteroaryl.

In another embodiment, a is 2 and each R₂ is independently selected from-halo, —OH, —NH₂, —CN, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or6-membered)heterocycle, -phenyl, -naphthalenyl or -(5- or6-membered)heteroaryl.

In another embodiment, a is 1 and R₂ is selected from -halo, —OH, —NH₂,—CN, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or 6-membered)heterocycle,-phenyl, -naphthalenyl or -(5- or 6-membered)heteroaryl.

In another embodiment, a is 2 and each R₂ is independently selected from-halo, —OH, —NH₂, —CN, methyl, ethyl, n-propyl, iso-propyl, cyclopentyl,cyclohexyl, cycloheptyl, or phenyl.

In another embodiment, a is 1 and R₂ is selected from -halo, —OH, —NH₂,—CN, methyl, ethyl, n-propyl, iso-propyl, cyclopentyl, cyclohexyl,cycloheptyl, or phenyl.

In another embodiment, a is 1 and R₂ is selected from -halo, optionally—F.

In another embodiment, Q is selected from benzo, pyridino, pyrimidino,pyrazino, pyridazino, pyrrolino, imidazolino, pyrazolino, triazolino,furano, oxazolino, isoxazolino, oxadiazolino, thiopheno, thiazolino,isothiazolino, or thiadiazolino.

In another embodiment, Q is selected from benzo or pyridino.

In another embodiment, a is 1, Q is benzo or pyridino, and R₂ isattached at the 6-position of the benzo or pyridino, e.g., asillustrated for the —F substituted benzo of Substituted-Quinoxaline-TypePiperidine Compound 133.

In another embodiment, a is 1, Q is benzo or pyridino, R₂ is selectedfrom -halo, optionally —F, and R₂ is attached at the 6-position of thebenzo or pyridino, e.g., as illustrated for the —F substituted benzo ofSubstituted-Quinoxaline-Type Piperidine Compound 133.

In another embodiment, Q is benzo.

In another embodiment, Q is pyridino.

In another embodiment, Q is pyridino and the 2- and 3-positions of thepyridino are fused to the 6-membered, nitrogen-containing ring, e.g. asillustrated for compounds according to Formula (JIB).

In another embodiment, each Y is O.

In another embodiment, each Y is S.

In another embodiment, the pharmaceutically acceptable derivative ofcompounds of Formula (II) is a pharmaceutically acceptable salt.

In another embodiment, the pharmaceutically acceptable salt is ahydrochloride salt.

In another embodiment, the pharmaceutically acceptable salt is a sodiumsalt.

In another embodiment, the pharmaceutically acceptable salt is apotassium salt.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIA):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (II).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIB):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (II).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIC):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (II).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IID):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (II).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IID1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula (HD)wherein the 6-membered, nitrogen-containing ring that is fused to thebenzo is in the endo- configuration with respect to the (—CH₂—CH₂—)bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IID2):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IID) wherein the 6-membered, nitrogen-containing ring that is fused tothe benzo is in the exo- configuration with respect to the (—CH₂—CH₂—)bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIE):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (II).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIE1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIE) wherein the 6-membered, nitrogen-containing ring that is fused tothe benzo is in the endo- configuration with respect to the(—CH₂—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIE2):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIE) wherein the 6-membered, nitrogen-containing ring that is fused tothe benzo is in the exo- configuration with respect to the(—CH₂—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIF):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (II).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIF1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIF) wherein the 6-membered, nitrogen-containing ring that is fused tothe pyridino is in the endo- configuration with respect to the(—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIF2):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIF) wherein the 6-membered, nitrogen-containing ring that is fused tothe pyridino is in the exo- configuration with respect to the(—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIG):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (II).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIG1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIG) wherein the 6-membered, nitrogen-containing ring that is fused tothe pyridino is in the endo- configuration with respect to the(—CH₂—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIG2):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound′ ompound ofFormula (IIG) wherein the 6-membered, nitrogen-containing ring that isfused to the pyridino is in the exo- configuration with respect to the(—CH₂—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIH):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (II).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIH1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIH) wherein the 6-membered, nitrogen-containing ring that is fused tothe pyridino is in the endo- configuration with respect to the(—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIH2):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIH) wherein the 6-membered, nitrogen-containing ring that is fused tothe pyridino is in the exo- configuration with respect to the(—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIJ):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (II).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIJ1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIJ) wherein the 6-membered, nitrogen-containing ring that is fused tothe pyridino is in the endo- configuration with respect to the(—CH₂—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIJ1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(III) wherein the 6-membered, nitrogen-containing ring that is fused tothe pyridino is in the exo- configuration with respect to the(—CH₂—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIK):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (II).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIL):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (II).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIM):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (II).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIN):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (II).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIN1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIN) wherein the 6-membered, nitrogen-containing ring that is fused tothe benzo is in the endo- configuration with respect to the (—CH₂—CH₂—)bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIN2):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIN) wherein the 6-membered, nitrogen-containing ring that is fused tothe benzo is in the exo- configuration with respect to the (—CH₂—CH₂—)bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIO):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (II).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIO1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIO) wherein the 6-membered, nitrogen-containing ring that is fused tothe benzo is in the endo- configuration with respect to the(—CH₂—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIO2):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIO) wherein the 6-membered, nitrogen-containing ring that is fused tothe benzo is in the exo- configuration with respect to the(—CH₂—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIP):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (H).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIP1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula (BP)wherein the 6-membered, nitrogen-containing ring that is fused to thepyridino is in the endo- configuration with respect to the (—CH₂—CH₂—)bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIP2):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula (BP)wherein the 6-membered, nitrogen-containing ring that is fused to thepyridino is in the exo- configuration with respect to the (—CH₂—CH₂—)bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIQ):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (II).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIQ1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIQ) wherein the 6-membered, nitrogen-containing ring that is fused tothe pyridino is in the endo- configuration with respect to the(—CH₂—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIQ2):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIQ) wherein the 6-membered, nitrogen-containing ring that is fused tothe pyridino is in the exo- configuration with respect to the(—CH₂—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIR):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (II).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIR1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIR) wherein the 6-membered, nitrogen-containing ring that is fused tothe pyridino is in the endo- configuration with respect to the(—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIR2):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIR) wherein the 6-membered, nitrogen-containing ring that is fused tothe pyridino is in the exo- configuration with respect to the(—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIS):

wherein R₁, R₂, R₄, Z and a are as defined above for theSubstituted-Quinoxaline-Type Piperidine Compounds of Formula (II).

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIS1):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIS) wherein the 6-membered, nitrogen-containing ring that is fused tothe pyridino is in the endo- configuration with respect to the(—CH₂—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is a Substituted-Quinoxaline-Type PiperidineCompound of Formula (IIS2):

i.e., a Substituted-Quinoxaline-Type Piperidine Compound of Formula(IIS) wherein the 6-membered, nitrogen-containing ring that is fused tothe pyridino is in the exo- configuration with respect to the(—CH₂—CH₂—CH₂—) bridge.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompound of Formula (II) is

4.3 Definitions

As used in connection with the Substituted-Quinoxaline-Type PiperidineCompounds herein, the terms used herein having following meaning:

“—(C₁-C₁₀)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 10 carbon atoms. Representative straightchain —(C₁-C₁₀)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl. Abranched alkyl means that one or more straight chain —(C₁-C₈)alkylgroups, such as methyl, ethyl or propyl, replace one or both hydrogensin a —CH₂— group of a straight chain alkyl. A branched non-cyclichydrocarbon means that one or more straight chain —(C₁-C₁₀)alkyl groups,such as methyl, ethyl or propyl, replace one or both hydrogens in a—CH₂— group of a straight chain non-cyclic hydrocarbon. Representativebranched —(C₁—C₁₀)alkyls include -iso-propyl, -sec-butyl, -iso-butyl,-tert-butyl, -iso-pentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl,2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl,4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl,1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl,1,2-dimethylheptyl, 1,3-dimethylheptyl, and 3,3-dimethylheptyl.

“—(C₁-C₆)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 6 carbon atoms. Representative straightchain —(C₁-C₆)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, and -n-hexyl. Representative branched —(C₁-C₆)alkyls include-iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl,-neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethtylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

“—(C₁-C₄)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 4 carbon atoms. Representative straightchain —(C₁-C₄)alkyls include -methyl, -ethyl, -n-propyl, and -n-butyl.Representative branched —(C₁-C₄)alkyls include -iso-propyl, -sec-butyl,-iso-butyl, and -tert-butyl.

“—(C₁-C₃)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 3 carbon atoms. Representative straightchain —(C₁-C₃)alkyls include -methyl, -ethyl, and -n-propyl.Representative branched —(C₁-C₃)alkyls include -iso-propyl.

“—(C₁-C₂)alkyl” means a straight chain non-cyclic hydrocarbon having 1or 2 carbon atoms. Representative straight chain —(C₁-C₂)alkyls include-methyl and -ethyl.

“—(C₂-C₁₀)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon double bond. A branched alkenyl means that one or morestraight chain —(C₁-C₈)alkyl groups, such as methyl, ethyl or propyl,replace one or both hydrogens in a —CH₂— or —CH═ group of a straightchain alkenyl. Representative straight chain and branched(C₂-C₁₀)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl,-3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl,-2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl,-2-decenyl, -3-decenyl, and the like.

“—(C₂-C₆)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon double bond. Representative straight chain and branched(C₂-C₆)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl,3-hexenyl, and the like.

“—(C₂-C₁₀)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon triple bond. A branched alkynyl means that one or morestraight chain —(C₁-C₈)alkyl groups, such as methyl, ethyl or propyl,replace one or both hydrogens in a —CH₂— group of a straight chainalkynyl. Representative straight chain and branched —(C₂-C₁₀)alkynylsinclude -acetylenyl, -propynyl, -1-butyryl, -2-butynyl, -1-pentynyl,-2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl,-5-hexynyl, -1-heptynyl, -2-heptynyl, -6-heptynyl, -1-octynyl,-2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl, -1-decynyl,-2-decynyl, -9-decynyl, and the like.

“—(C₂-C₆)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon triple bond. Representative straight chain and branched(C₂-C₆)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl,-1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl,-2-hexynyl, -5-hexynyl, and the like.

“—(C₁-C₆)alkoxy” means a straight chain or branched non-cyclichydrocarbon having one or more ether groups and from 1 to 6 carbonatoms. Representative straight chain and branched (C₁-C₆)alkoxys include-methoxy, -ethoxy, methoxymethyl, 2-methoxyethyl, -5-methoxypentyl,3-ethoxybutyl and the like.

“—(C₃-C₁₄)cycloalkyl” means a saturated monocyclic hydrocarbon havingfrom 3 to 14 carbon atoms. Representative (C₃-C₁₄)cycloalkyls are-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl,-cyclooctyl, -cyclononyl, -cyclodecyl, cycloundecyl, and -cyclododecyl,and -cyclotetradecyl.

“—(C₃-C₁₂)cycloalkyl” means a saturated monocyclic hydrocarbon havingfrom 3 to 12 carbon atoms. Representative (C₃-C₁₂)cycloalkyls are-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl,-cyclooctyl, -cyclononyl, -cyclodecyl, cycloundecyl, and -cyclododecyl.

“—(C₆-C₁₂)cycloalkyl” means a saturated monocyclic hydrocarbon havingfrom 6 to 12 carbon atoms. Representative (C₆-C₁₂)cycloalkyls are-cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl, -cyclodecyl,cycloundecyl, and -cyclododecyl.

“—(C₄-C₈)cycloalkyl” or “4- to 8-member cycloalkyl ring” means asaturated monocyclic hydrocarbon having from 4 to 8 carbon atoms.Representative —(C₄-C₈)cycloalkyls are -cyclobutyl, -cyclopentyl,-cyclohexyl, -cycloheptyl, and -cyclooctyl.

“—(C₃-C₈)cycloalkyl” means a saturated monocyclic hydrocarbon havingfrom 3 to 8 carbon atoms. Representative (C₃-C₈)cycloalkyls include-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and-cyclooctyl.

“—(C₃-C₇)cycloalkyl” means a saturated monocyclic hydrocarbon havingfrom 3 to 7 carbon atoms. Representative (C₃-C₇)cycloalkyls includecyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, and -cycloheptyl.

“—(C₆-C₁₄)bicycloalkyl” means a bi-cyclic hydrocarbon ring system havingfrom 6 to 14 carbon atoms and at least one saturated cyclic alkyl ring.Representative —(C₆-C₁₄)bicycloalkyls include -indanyl, -norbornyl,-1,2,3,4-tetrahydronaphthalenyl, -5,6,7,8-tetrahydronaphthalenyl,-perhydronaphthalenyl, bicyclo[2.2.1]hexyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.2]octyl, bicyclo[3.3.1]heptyl, bicyclo[3.2.1]octyl,bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl,bicyclo[4.2.2]decyl, bicyclo[4.3.2]undecyl, bicyclo[4.3.1]decyl, and thelike.

“—(C₈-C₂₀)tricycloalkyl” means a tri-cyclic hydrocarbon ring systemhaving from 8 to 20 carbon atoms and at least one saturated cyclic alkylring. Representative —(C₈-C₂₀)tricycloalkyls include -pyrenyl,-adamantyl, noradamantyl, -1,2,3,4-tetrahydroanthracenyl,-perhydroanthracenyl -aceanthrenyl, -1,2,3,4-tetrahydropenanthrenyl,-5,6,7,8-tetrahydrophenanthrenyl, -perhydrophenanthrenyl,tetradecahydro-1H-cyclohepta[a]naphthalenyl,tetradecahydro-1H-cycloocta[e]indenyl,tetradecahydro-1H-cyclohepta[e]azulenyl,hexadecahydrocycloocta[b]naphthalenyl,hexadecahydrocyclohepta[a]heptalenyl, tricyclo-pentadecanyl,tricyclo-octadecanyl, tricyclo-nonadecanyl, tricyclo-icosanyl, and thelike.

“—(C₃-C₁₄)cycloalkenyl” means a cyclic non-aromatic hydrocarbon havingat least one carbon-carbon double bond in the cyclic system and from 3to 14 carbon atoms. Representative (C₃-C₁₄)cycloalkenyls include-cyclopropenyl, -cyclobutenyl, -cyclopentenyl, -cyclopentadienyl,-cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl,-cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl,-cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl, -cyclodecenyl,-cyclodecadienyl, -cyclotetradecenyl, -cyclododecadienyl, and the like.

“—(C₅-C₁₄)cycloalkenyl” means a cyclic non-aromatic hydrocarbon havingat least one carbon-carbon double bond in the cyclic system and from 5to 14 carbon atoms. Representative (C₅-C₁₄)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl,-cyclononadienyl, -cyclodecenyl, -cyclodecadienyl, -cyclotetradecenyl,-cyclododecadienyl, and the like.

“—(C₆-C₁₂)cycloalkenyl” means a cyclic non-aromatic hydrocarbon havingat least one carbon-carbon double bond in the cyclic system and from 6to 12 carbon atoms. Representative (C₆-C₁₂)cycloalkenyls include-cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl,-cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl,-cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl, -cyclodecenyl,-cyclodecadienyl, -cyclododecadienyl, and the like.

“—(C₅-C₁₀)cycloalkenyl” means a cyclic non-aromatic hydrocarbon havingat least one carbon-carbon double bond in the cyclic system and from 5to 10 carbon atoms. Representative (C₅-C₁₀)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl,-cyclononadienyl, -cyclodecenyl, -cyclodecadienyl, and the like.

“—(C₅-C₈)cycloalkenyl” means a cyclic non-aromatic hydrocarbon having atleast one carbon-carbon double bond in the cyclic system and from 5 to 8carbon atoms. Representative (C₅-C₈)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, and the like.

“—(C₇-C₁₄)bicycloalkenyl” means a bi-cyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and from 7 to14 carbon atoms. Representative —(C₇-C₁₄)bicycloalkenyls include-bicyclo[3.2.0]hept-2-enyl, -indenyl, -pentalenyl, -naphthalenyl,-azulenyl, -heptalenyl, -1,2,7,8-tetrahydronaphthalenyl, norbornenyl,and the like.

“—(C₈-C₂₀)tricycloalkenyl” means a tri-cyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and from 8 to20 carbon atoms. Representative —(C₈-C₂₀)tricycloalkenyls include-anthracenyl, -phenanthrenyl, -phenalenyl, -acenaphthalenyl,as-indacenyl, s-indacenyl,2,3,6,7,8,9,10,11-octahydro-1H-cycloocta[e]indenyl,2,3,4,7,8,9,10,11-octahydro-1H-cyclohepta[a]naphthalenyl,8,9,10,11-tetrahydro-7H-cyclohepta[a]naphthalenyl,2,3,4,5,6,7,8,9,10,11,12,13-dodecahydro-1H-cyclohepta[a]heptalenyl,1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-dicyclohepta[a,c]cyclooctenyl,2,3,4,5,6,7,8,9,10,11,12,13-dodecahydro-1H-dibenzo[a,d]cyclononenyl, andthe like.

“-(3- to 7-membered)heterocycle” or “-(3- to 7-membered)heterocyclo”means a 3- to 7-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 3-memberedheterocycle can contain up to 1 heteroatom, a 4-membered heterocycle cancontain up to 2 heteroatoms, a 5-membered heterocycle can contain up to4 heteroatoms, a 6-membered heterocycle can contain up to 4 heteroatoms,and a 7-membered heterocycle can contain up to 5 heteroatoms. Eachheteroatom is independently selected from nitrogen, which can bequaternized; oxygen; and sulfur, including sulfoxide and sulfone. The-(3- to 7-membered)heterocycle can be attached via a nitrogen or carbonatom. Representative -(3- to 7-membered)heterocycles include pyridyl,furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl,thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl,pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl,dihydropyranyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl,tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, and the like.

“-(5- or 6-membered)heterocycle” or “-(5- or 6-membered)heterocyclo”means a 5- or 6-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 5-memberedheterocycle can contain up to 4 heteroatoms and a 6-membered heterocyclecan contain up to 4 heteroatoms. Each heteroatom is independentlyselected from nitrogen, which can be quaternized; oxygen; and sulfur,including sulfoxide and sulfone. The -(5- or 6-membered)heterocycle canbe attached via a nitrogen or carbon atom. Representative -(5- or6-membered)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl,oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl,isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl,triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, hydantoinyl,valerolactamyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl,tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, tetrazolyl, and the like.

“-(3- to 5-membered)heterocycle” or “-(3- to 5-membered)heterocyclo”means a 3- to 5-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 3-memberedheterocycle can contain up to 1 heteroatom, a 4-membered heterocycle cancontain up to 2 heteroatoms, and a 5-membered heterocycle can contain upto 4 heteroatoms. Each heteroatom is independently selected fromnitrogen, which can be quaternized; oxygen; and sulfur, includingsulfoxide and sulfone. The -(3- to 5-membered)heterocycle can beattached via a nitrogen or carbon atom. Representative -(3- to5-membered)heterocycles include furyl, thiophenyl, pyrrolyl, oxazolyl,imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl,pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl, pyrrolidinyl,2,3-dihydrofuranyl, hydantoinyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrazolidinyl and the like.

“-(7- to 10-membered)bicycloheterocycle” or “-(7- to10-membered)bicycloheterocyclo” means a 7- to 10-membered bicyclic,heterocyclic ring which is either saturated, unsaturated non-aromatic,or aromatic. A -(7- to 10-membered)bicycloheterocycle contains from 1 to4 heteroatoms independently selected from nitrogen, which can bequaternized; oxygen; and sulfur, including sulfoxide and sulfone. The-(7- to 10-membered)bicycloheterocycle can be attached via a nitrogen orcarbon atom. Representative -(7- to 10-membered)bicycloheterocyclesinclude -quinolinyl, -isoquinolinyl, -chromonyl, -coumarinyl, -indolyl,-indolizinyl, -benzo[b]furanyl, -benzo[b]thiophenyl, -indazolyl,-purinyl, -4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl,-naphthyridinyl, -carbazolyl, carbolinyl, -indolinyl, -isoindolinyl,-1,2,3,4-tetrahydroquinolinyl, -1,2,3,4-tetrahydroisoquinolinyl,pyrrolopyrrolyl and the like.

“—(C₃-C₁₂)cycloalkoxy” means a saturated monocyclic hydrocarbon havingfrom 3 to 12 carbon atoms where at least one of the carbon atoms isreplaced by an oxygen atom. Representative (C₃-C₁₂)cycloalkoxy are-oxiranyl, -oxetanyl, -tetrahydrofuranyl, -tetrahydro-2H-pyranyl,-1,4-dioxanyl, -oxepanyl, -1,4-dioxepanyl, -oxocanyl, -1,5-dioxocanyl,-1,3,5-trioxocanyl, -oxonanyl, -1,5-dioxonanyl, -1,4,7-trioxonanyl,-oxacyclododecanyl, -1,7-dioxacyclododecanyl, and-1,5,9-trioxacyclododecanyl.

“—(C₃-C₇)cycloalkoxy” means a saturated monocyclic hydrocarbon havingfrom 3 to 7 carbon atoms where at least one of the carbon atoms isreplaced by an oxygen atom. Representative (C₃-C₇)cycloalkoxy are-oxiranyl, -oxetanyl, -tetrahydrofuranyl, -tetrahydro-2H-pyranyl,-1,4-dioxanyl, -oxepanyl, and -1,4-dioxepanyl.

“—(C₁₄)aryl” means a 14-membered aromatic carbocyclic moiety such as-anthryl or -phenanthryl.

“-(5- to 10-membered)heteroaryl” means an aromatic heterocycle ring of 5to 10 members, including both mono- and bicyclic ring systems, where atleast one carbon atom of one or both of the rings is replaced with aheteroatom independently selected from nitrogen, oxygen, and sulfur, orat least two carbon atoms of one or both of the rings are replaced witha heteroatom independently selected from nitrogen, oxygen, and sulfur.In one embodiment, one of the -(5- to 10-membered)heteroaryl's ringscontain at least one carbon atom. In another embodiment, both of the-(5- to 10-membered)heteroaryl's rings contain at least one carbon atom.Representative -(5- to 10-membered)heteroaryls include pyridyl, furyl,benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, isoquinolinyl,pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl,thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolinyl, pyrazolyl,isothiazolyl, pyridazinyl, pyrimidyl, pyrimidinyl, pyrazinyl,thiadiazolyl, triazinyl, thienyl, cinnolinyl, phthalazinyl, andquinazolinyl.

“-(5- or 6-membered)heteroaryl” means a monocyclic aromatic heterocyclering of 5 or 6 members where at least one carbon atom is replaced with aheteroatom independently selected from nitrogen, oxygen, and sulfur. Inone embodiment, one of the -(5- or 6-membered)heteroaryl's ring containsat least one carbon atom. Representative -(5- or 6-membered)heteroarylsinclude pyridyl, furyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl,isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl,pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,5-triazinyl, and thiophenyl.

“—CH₂(halo)” means a methyl group where one of the hydrogens of themethyl group has been replaced with a halogen. Representative —CH₂(halo)groups include —CH₂F, —CH₂Cl, —CH₂Br, and —CH₂I.

“—CH(halo)₂” means a methyl group where two of the hydrogens of themethyl group have been replaced with a halogen. Representative—CH(halo)₂ groups include —CHF₂, —CHCl₂, —CHBr₂, —CHBrCI, —CHClI, and—CHI₂.

“—C(halo)₃” means a methyl group where each of the hydrogens of themethyl group has been replaced with a halogen. Representative —C(halo)₃groups include —CF₃, —CCl₃, —CBr₃, and —Cl₃.

“—Halogen” or “-halo” means —F, —Cl, —Br, or —I.

“Oxo”, “═O”, and the like as used herein mean an oxygen atom doublybonded to carbon or another element.

“Thiooxo”, “thioxo”, “═S”, and the like as used herein mean a sulfuratom doubly bonded to carbon or another element.

As used herein in connection with Formula (II), when the dashed line inthe 6-membered, nitrogen-containing ring that is fused to the Q group isabsent, then Formula (II) is understood to appear as follows

i.e., the 6-membered, nitrogen-containing ring that is fused to the Qgroup contains no double bond between the ring-carbon to which the R₄groups are attached and the adjacent ring-nitrogen.

As used herein in connection with Formula (II), when the dashed line inthe 6-membered, nitrogen-containing ring that is fused to the Q groupindicates the presence of a bond, then Formula (II) is understood toappear as follows

i.e., the 6-membered, nitrogen-containing ring that is fused to the Qgroup contains a double bond between the ring-carbon to which the R₄group is attached and the adjacent ring-nitrogen.

As used herein in connection with the R₁ group

when the dashed line in the ring indicates the presence of a bond, thenthat group is understood to appear as follows

and when the dashed line in the ring indicates the absence of a bond,then that group is understood to appear as follows

“—[(C₁-C₁₀)alkyl optionally substituted by R₁]_(h)—” as used herein inconnection with Z means that, when h is 0, Z is a bond. When h is 1,Z—R₁, as attached to the piperidine ring bearing A and B substituents,is

where; when i is 0, the (C₁-C₁₀)alkyl is unsubstituted by an R₁ group atany position other than at the carbon atom furthest removed from thepiperidine ring bearing A and B substituents; and, when i is 1, (i.e.,the (C₁-C₁₀)alkyl is optionally substituted by an R₁ group at the carbonatom furthest removed from the piperidine ring bearing A and Bsubstituents and substituted by another independently selected R₁ groupat any carbon atom of the (C₁-C₁₀)alkyl including at the carbon atomfurthest removed from the piperidine ring bearing A and B substituents.

“—[(C₁-C₁₀)alkenyl optionally substituted by R₁]—” as used herein inconnection with Z means that the piperidine ring bearing A and Bsubstituents, is

where; when i is 0, the (C₁-C₁₀)alkenyl is unsubstituted by an R₁ groupat any position other than at the carbon atom furthest removed from thepiperidine ring bearing A and B substituents; and, when i is 1, (i.e.,the (C₁-C₁₀)alkenyl is optionally substituted by an R₁ group at thecarbon atom furthest removed from the piperidine ring bearing A and Bsubstituents and substituted by another independently selected R₁ groupat any carbon atom of the (C₁-C₁₀)alkenyl including at the carbon atomfurthest removed from the piperidine ring bearing A and B substituents.

“(C₂-C₆)bridge” as used herein means a hydrocarbon chain containing 2 to6 carbon atoms joining two atoms of the piperidine ring of Formula (I)or Formula (II) to form a fused bicyclic ring system. For example,compounds of the invention can comprise a (C₂-C₆)bridge joiningpositions 2 and 6 of the piperidine ring (A-B can together form a(C₂-C₆)bridge). Exemplary compounds of the invention include those withan unsubstituted (C₂)bridge, —CH₂—CH₂—, joining positions 2 and 6 of thepiperidine ring (A-B can together form a (C₂)bridge); an unsubstituted(C₃)bridge, —CH₂—CH₂—CH₂—, joining positions 2 and 6 of the piperidinering (A-B can together form a (C₃)bridge); an unsubstituted (C₄)bridge,—CH₂—CH₂—CH₂—CH₂—, joining positions 2 and 6 of the piperidine ring (A-Bcan together form a (C₄)bridge); an unsubstituted (C₅)bridge,—CH₂—CH₂—CH₂—CH₂—CH₂—, joining positions 2 and 6 of the piperidine ring(A-B can together form a (C₅)bridge); or an unsubstituted (C₆)bridge,—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—, joining positions 2 and 6 of the piperidinering (A-B can together form a (C₆)bridge). Examples of compounds whereA-B can together form a (C₂-C₆)bridge include compounds comprising thefollowing ring systems: 8-aza-bicyclo[3.2.1]octane;9-aza-bicyclo[3.3.1]nonane; 10-aza-bicyclo[4.3.1]decane;11-aza-bicyclo[5.3.1]undecane; and 12-aza-bicyclo[6.3.1]dodecane.Examples of a (C₂-C₆)bridge which optionally contains —HC═CH— within the(C₂-C₆)bridge include —HC═CH—, —CH₂—HC═CH—, —HC═CH—CH₂—,—CH₂—HC═CH—CH₂—, and the like. Examples of a (C₂-C₆)bridge whichoptionally contains —O— within the (C₂-C₆)bridge include —CH₂—O—CH₂—(containing 2 carbon atoms), —CH₂—O—CH₂—CH₂— and —CH₂—CH₂—O—CH₂— (eachcontaining 3 carbon atoms), —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—CH₂— and—CH₂—CH₂—CH₂—O—CH₂— (each containing 4 carbon atoms), and the like.

In compounds of the invention comprising a bridge joining positions 2and 6 of the piperidine ring (e.g., A-B can together form a(C₂-C₆)bridge), for, e.g., a compound of Formula (II), the exemplaryendo bridge

is equivalent to

In compounds of the invention comprising a bridge joining positions 2and 6 of the piperidine ring (e.g., A-B can together form a(C₂-C₆)bridge), for, e.g., a compound of Formula (II), the exemplary exobridge

is equivalent to

In compounds of the invention where the —Z—R₁ group comprises a bicyclicgroup, that bicyclic group can have two orientations. For example, for a—Z—R₁ group that is a —(C₆-C₁₄)bicycloalkyl, e.g.,bicyclo[3.3.1]nonanyl, attached directly to the piperidine ringnitrogen, the following orientations are possible:

When a first group is “substituted with one or more” second groups, oneor more hydrogen atoms of the first group is replaced with acorresponding number of second groups. When the number of second groupsis two or greater, each second group can be the same or different.

In one embodiment, a first group is substituted with up to three secondgroups.

In another embodiment, a first group is substituted with one or twosecond groups.

In another embodiment, a first group is substituted with only one secondgroup.

The phrase “benzo”, “benzo group” and the like, when used in connectionwith the optionally-substituted Q group, means

where R₂ and a are defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II).

The phrase “pyridino”, “pyridino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II). In one embodiment, theoptionally-substituted pyridino Q group is

In another embodiment, the optionally-substituted pyridino Q group is

In another embodiment, the optionally-substituted pyridino Q group is

In another embodiment, the optionally-substituted pyridino Q group is

The phrase “pyrimidino”, “pyrimidino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II). In one embodiment, theoptionally-substituted pyrimidino Q group is

In another embodiment, the optionally-substituted pyrimidino Q group is

The phrase “pyrazino”, “pyrazino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II).

The phrase “pyridazino”, “pyridazino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II). In one embodiment, theoptionally-substituted pyridazino Q group is

In another embodiment, the optionally-substituted pyridazino Q group is

In another embodiment, the optionally-substituted pyridazino Q group is

In one embodiment, the phrase “optionally substitutedbicyclo[3.3.1]nonyl”, when used in connection with theoptionally-substituted R₁ group, means

where R_(z) is defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II).

In one embodiment the optionally substituted bicyclo[3.3.1]nonyl is

In another embodiment the optionally substituted bicyclo[3.3.1]nonly is

In another embodiment the optionally substituted bicyclo[3.3.1]nonly is

In another embodiment the optionally substituted bicyclo[3.3.1]nonly is

In another embodiment the optionally substituted bicyclo[3.3.1]nonly is

In one embodiment the phrase “optionally substituted—(C₆-C₁₄)bicycloalkyl” means

wherein the dashed line denotes the presence or absence of a bond.

The phrase “pyrrolino”, “pyrrolino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II). In one embodiment, theoptionally-substituted pyrrolino Q group is

In another embodiment, the optionally-substituted pyrrolino. Q group is

In another embodiment, the optionally-substituted pyrrolino Q group is

The phrase “imidazolino”, “imidazolino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II). In one embodiment, theoptionally-substituted imidazolino Q group is

In another embodiment, the optionally-substituted imidazolino Q group is

The phrase “pyrazolino”, “pyrazolino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II). In one embodiment, theoptionally-substituted pyrazolino Q group is

In another embodiment, the optionally-substituted pyrazolino Q group is

In another embodiment, the optionally-substituted pyrazolino Q group is

In another embodiment, the optionally-substituted pyrazolino Q group is

The phrase “triazolino”, “triazolino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II). In one embodiment, theoptionally-substituted triazolino Q group is

In another embodiment, the optionally-substituted triazolino Q group is

The phrase “furano”, “furano group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II). In one embodiment, theoptionally-substituted furano Q group is

In another embodiment, the optionally-substituted furano Q group is

In another embodiment, the optionally-substituted furano Q group is

The phrase “oxazolino”, “oxazolino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II). In one embodiment, theoptionally-substituted oxazolino Q group is

In another embodiment, the optionally-substituted oxazolino Q group is

The phrase “isoxazolino”, “isoxazolino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II). In one embodiment, theoptionally-substituted isoxazolino Q group is

In another embodiment, the optionally-substituted isoxazolino Q group is

In another embodiment, the optionally-substituted isoxazolino Q group is

In another embodiment, the optionally-substituted isoxazolino Q group is

The phrase “oxadiazolino”, “oxadiazolino group” and the like, when usedin connection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II). In one embodiment, theoptionally-substituted oxadiazolino Q group is

In another embodiment, the optionally-substituted oxadiazolino Q groupis

In another embodiment, the optionally-substituted oxadiazolino Q groupis

The phrase “thiopheno”, “thiopheno group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II). In one embodiment, theoptionally-substituted thiopheno Q group is

In another embodiment, the optionally-substituted thiopheno Q group is

In another embodiment, the optionally-substituted thiopheno Q group is

The phrase “thiazolino”, “thiazolino group” and the like, when used inconnection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II). In one embodiment, theoptionally-substituted thiazolino Q group is

In another embodiment, the optionally-substituted thiazolino Q group is

The phrase “isothiazolino”, “isothiazolino group” and the like, whenused in connection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II). In one embodiment, theoptionally-substituted isothiazolino Q group is

In another embodiment, the optionally-substituted isothiazolino Q groupis

In another embodiment, the optionally-substituted isothiazolino Q groupis

In another embodiment, the optionally-substituted isothiazolino Q groupis

The phrase “thiadiazolino”, “thiadiazolino group” and the like, whenused in connection with the optionally-substituted Q group, means

where R₂ and a are defined above for the Substituted-Quinoxaline-TypePiperidine Compounds of Formulas (I) and (II). In one embodiment, theoptionally-substituted thiadiazolino Q group is

In another embodiment, the optionally-substituted thiadiazolino Q groupis

In another embodiment, the optionally-substituted thiadiazolino Q groupis

The phrase “3,3-diphenylpropyl-” and the like, when used in connectionwith the —Z—R₁ group, means

where the 3 carbon of the propyl is indicated by the number 3 in thestructure above.

The phrase “tetrazolyl group” means

In one embodiment, the tetrazolyl group is

In another embodiment, the tetrazolyl group is

The term “animal” includes, but is not limited to, a human or anon-human animal, such as a companion animal or livestock, e.g., a cow,monkey, baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail,cat, dog, mouse, rat, rabbit or guinea pig.

The phrase “pharmaceutically acceptable derivative”, as used herein,includes any pharmaceutically acceptable salt, solvate, prodrug,radiolabeled, stereoisomer, enantiomer, diastereomer, otherstereoisomeric form, racemic mixture, geometric isomer, and/or tautomer,e.g., of a Substituted-Quinoxaline-Type Piperidine Compound of theinvention. In one embodiment, the pharmaceutically acceptable derivativeis a pharmaceutically acceptable salt, solvate, radiolabeled,stereoisomer, enantiomer, diastereomer, other stereoisomeric form,racemic mixture, geometric isomer, and/or tautomer, e.g., of aSubstituted-Quinoxaline-Type Piperidine Compound of the invention. Inanother embodiment, the pharmaceutically acceptable derivative is apharmaceutically acceptable salt, e.g., of aSubstituted-Quinoxaline-Type Piperidine Compound of the invention.

The phrase “pharmaceutically acceptable salt”, as used herein, is anypharmaceutically acceptable salt that can be prepared from aSubstituted-Quinoxaline-Type Piperidine Compound including a salt formedfrom an acid and a basic functional group, such as a nitrogen group, ofa Substituted-Quinoxaline-Type Piperidine Compound. Illustrative saltsinclude, but are not limited, to sulfate, citrate, acetate,trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucoronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.The term “pharmaceutically acceptable salt” also includes a saltprepared from a Substituted-Quinoxaline-Type Piperidine Compound havingan acidic functional group, such as a carboxylic acid functional group,and a pharmaceutically acceptable inorganic or organic base. Suitablebases include, but are not limited to, hydroxides of alkali metals suchas sodium, potassium, cesium, and lithium; hydroxides of alkaline earthmetal such as calcium and magnesium; hydroxides of other metals, such asaluminum and zinc; ammonia and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; picoline; N-methyl,N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-(C₁-C₃)alkyl amines),such as mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N-di-[(C₁-C₃)alkyl]-N-(hydroxy-(C₁-C₃)alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. One skilled in the art will recognize that, e.g., acid additionsalts of a Substituted-Quinoxaline-Type Piperidine Compound can beprepared by reaction of the compounds with the appropriate acid via avariety of known methods.

The invention disclosed herein is also meant to encompass all solvatesof the Substituted-Quinoxaline-Type Piperidine Compounds. “Solvates” areknown in the art and are considered to be a combination, physicalassociation and/or solvation of a Substituted-Quinoxaline-TypePiperidine Compound with a solvent molecule, e.g., a disolvate,monosolvate or hemisolvate when the solvent molecule:Substituted-Quinoxaline-Type Piperidine Compound molecule ratio is 2:1,1:1 or 1:2, respectively. This physical association involves varyingdegrees of ionic and covalent bonding, including hydrogen bonding. Incertain instances, the solvate can be isolated, for example when one ormore solvent molecules are incorporated into the crystal lattice of acrystalline solid. Thus, “solvate”, as used herein, encompasses bothsolution-phase and isolatable solvates. A Substituted-Quinoxaline-TypePiperidine Compound of the invention can be present as a solvated formwith a pharmaceutically acceptable solvent, such as water, methanol,ethanol, and the like, and it is intended that the invention includeboth solvated and unsolvated Substituted-Quinoxaline-Type PiperidineCompound forms. As “hydrate” relates to a particular subgroup ofsolvates, i.e., where the solvent molecule is water, hydrates areincluded within the solvates of the invention. Preparation of solvatesis known in the art. For example, M. Caira et al., J. Pharmaceut. Sci.,93(3):601-611 (2004), describes the preparation of solvates offluconazole with ethyl acetate and with water. Similar preparations ofsolvates, hemisolvate, hydrates, and the like are described by E. C. vanTonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004), and A. L.Bingham et al., Chem. Commun., 603-604 (2001). A typical, non-limiting,process involves dissolving the Substituted-Quinoxaline-Type PiperidineCompound in a desired amount of the desired solvent (organic, water ormixtures thereof) at temperatures above about 20° C. to about 25° C.,cooling the solution at a rate sufficient to form crystals, andisolating the crystals by known methods, e.g., filtration. Analyticaltechniques, for example, infrared spectroscopy, can be used to show thepresence of the solvent in a crystal of the solvate.

The invention disclosed herein is also meant to encompass all prodrugsof the Substituted-Quinoxaline-Type Piperidine Compounds. “Prodrugs” areknown in the art and, while not necessarily possessing anypharmaceutical activity as such, are considered to be any covalentlybonded carrier(s) that releases the active parent drug in vivo. Ingeneral, such prodrugs will be a functional derivative of aSubstituted-Quinoxaline-Type Piperidine Compound of Formula (I) orFormula (II) which is readily convertible in vivo, e.g., by beingmetabolized, into the required Substituted-Quinoxaline-Type PiperidineCompound of Formula (I) or Formula (II). Conventional procedures for theselection and preparation of suitable prodrug derivatives are describedin, for example, Design of Prodrugs, H. Bundgaard ed., Elsevier (1985);“Drug and Enzyme Targeting, Part A,” K. Widder et al. eds., Vol. 112 inMethods in Enzymology, Academic Press (1985); Bundgaard, “Design andApplication of Prodrugs,” Chapter 5 (pp. 113-191) in A Textbook of DrugDesign and Development, P. Krogsgaard-Larsen and H. Bundgaard eds.,Harwood Academic Publishers (1991); Bundgaard et al., Adv. Drug DeliveryRevs. 8:1-38 (1992); Bundgaard et al., J. Pharmaceut. Sci. 77:285(1988); and Kakeya et al., Chem. Pharm. Bull. 32:692 (1984).

In addition, one or more hydrogen, carbon or other atoms of aSubstituted-Quinoxaline-Type Piperidine Compound can be replaced by anisotope of the hydrogen, carbon or other atoms. Such a “radiolabeled”,“radiolabeled form”, and the like of a Substituted-Quinoxaline-TypePiperidine Compound, each of which is encompassed by the invention, isuseful as a research and/or diagnostic tool in metabolismpharmacokinetic studies and in binding assays. Examples of isotopes thatcan be incorporated into a Substituted-Quinoxaline-Type PiperidineCompound of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²F, ³⁵S, ¹⁸F, and ³⁶Cl,respectively. Radiolabeled compounds of the invention can be prepared bymethods known in the art. For example, tritiated compounds of Formula Ican be prepared by introducing tritium into the particular compound ofFormula I, for example, by catalytic dehalogenation with tritium. Thismethod can include reacting a suitably halogen-substituted precursor ofa compound of Formula (I) or Formula (II) with tritium gas in thepresence of a suitable catalyst, for example, Pd/C, in the presence orabsence of a base. Other suitable methods for preparing tritiatedcompounds can be found in Filer, Isotopes in the Physical and BiomedicalSciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987).¹⁴C-labeled compounds can be prepared by employing starting materialshaving a ¹⁴C carbon.

A Substituted-Quinoxaline-Type Piperidine Compound can contain one ormore asymmetric centers and can thus give rise to enantiomers,diastereomers, and other stereoisomeric forms. The invention is alsomeant to encompass all such possible forms as well as their racemic andresolved forms or any mixture thereof. When aSubstituted-Quinoxaline-Type Piperidine Compound contains an olefinicdouble bond or other center of geometric asymmetry, and unless specifiedotherwise, it is intended to include all “geometric isomers”, e.g., bothE and Z geometric isomers. All “tautomers”, e.g., ketone-enol,amide-imidic acid, lactam-lactim, enamine-imine, amine-imine, andenamine-enimine tautomers, are intended to be encompassed by theinvention as well.

As used herein, the terms “stereoisomer”, “stereoisomeric form”, and thelike are general terms for all isomers of individual molecules thatdiffer only in the orientation of their atoms in space. It includesenantiomers and isomers of compounds with more than one chiral centerthat are not mirror images of one another (“diastereomers”).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposeable on its mirror image and hence optically active wherethe enantiomer rotates the plane of polarized light in one direction andits mirror image rotates the plane of polarized light in the oppositedirection.

The term “racemic” refers to a mixture of equal parts of enantiomerswhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

Optical isomers of a Substituted-Quinoxaline-Type Piperidine Compoundcan be obtained by known techniques such as chiral chromatography orformation of diastereomeric salts from an optically active acid or base.

The phrase “effective amount”, when used in connection with aSubstituted-Quinoxaline-Type Piperidine Compound, means an amounteffective for: (a) treating or preventing a Condition; (b) detectablyinhibiting ORL-1 receptor function in a cell; or (c) detectablyactivating ORL-1 receptor function in a cell.

The phrase “effective amount”, when used in connection with a secondtherapeutic agent means an amount for providing the therapeutic effectof the therapeutic agent.

The terms “modulate”, “modulating”, and the like as used herein withrespect to the ORL-1 receptor mean the mediation of a pharmacodynamicresponse (e.g., analgesia) in an animal from (i) inhibiting oractivating the receptor, or (ii) directly or indirectly affecting thenormal regulation of the receptor activity. Compounds that modulate thereceptor activity include agonists, partial agonists, antagonists, mixedagonists/antagonists, mixed partial agonists/antagonists and compoundswhich directly or indirectly affect regulation of the receptor activity.

As used herein, a compound that binds to a receptor and mimics theregulatory effect(s) of an endogenous ligand is defined as an “agonist”.As used herein, a compound that binds to a receptor and is only partlyeffective as an agonist is defined as a “partial agonist”. As usedherein, a compound that binds to a receptor but produces no regulatoryeffect, but rather blocks binding of another agent to the receptor isdefined as an “antagonist”. (See Ross and Kenakin, Pharmacodynamics:Mechanisms of Drug Action and the Relationship Between DrugConcentration and Effect, Chapter 2 in. Goodman & Gilman's ThePharmacological Basis of Therapeutics 31-32 (J. G. Hardman, L. E.Limbird and A. Goodman-Gilman eds., 10^(th) ed 2001).

The term “MeOH” means methanol, i.e., methyl alcohol.

The term “EtOH” means ethanol, i.e., ethyl alcohol.

The term “Et₂O” means diethyl ether, i.e., ethoxyethane.

The term “THF” means tetrahydrofuran.

The term “DMF” means N,N-dimethylformamide.

The term “DCM” means methylene chloride, i.e., dichloromethane orCH₂Cl₂.

The term “DCE” means dichloroethane.

The term “EtOAc” means ethyl acetate.

The term “MeCN” means acetonitrile.

The term “DMSO” means dimethylsulfoxide, i.e., methylsulfinylmethane.

The term “AcOH” means acetic acid.

The term “NH₄Cl” means ammonium chloride.

The term “NH₄OH” means ammonium hydroxide.

The term “TEA” means triethylamine.

The term “TMA” means trimethylamine.

The term “DIEA” means N,N-di-iso-propylethylamine orN-ethyl-N-iso-propylpropan-2-amine.

The term “NaH” means sodium hydride.

The term “DMAP” means 4-dimethylaminopyridine.

The term “HOBT” means 1-hydroxybenzotriazole.

The term “WSCI” means a water soluble carbodiimide, for example,N-ethyl-N-(3-dimethylaminopropyl)carbodiimide.

The term “DIC” means 1,3-diisopropylcarbodiimide, i.e.,N,N′-methanediylidenedipropan-2-amine.

The term “TMSCl” means trimethylsilylchloride or (CH₃)₃SiCl.

The term “TFFA” means trifluoroacetic anhydride or 2,2,2-trifluoroaceticanhydride.

The term “Bn” means benzyl or

The term “BOC” means tert-butyloxycarbonyl or

The term “CBZ” means benzyloxycarbonyl or

The term “IBD” means inflammatory-bowel disease.

The term “IBS” means irritable-bowel syndrome.

The term “ALS” means amyotrophic lateral sclerosis.

The phrases “treatment of”, “treating”, and the like include theamelioration or cessation of a Condition or a symptom thereof. In oneembodiment, treating includes inhibiting, for example, decreasing theoverall frequency of episodes of a Condition or a symptom thereof.

The phrases “prevention of”, “preventing”, and the like include theavoidance of the onset of a Condition or a symptom thereof.

A “disorder” includes, but is not limited to, the Conditions definedabove.

4.4 Methods for Making the Substituted-Quinoxaline-Type PiperidineCompounds

The Substituted-Quinoxaline-Type Piperidine Compounds can be made usingconventional organic synthesis, in view of the present disclosure, andincluding the following illustrative methods shown in the schemes belowwhere R₁, R₂, R₃, R₄, T₁, T₂, T₃, Q, Y₁, Y, Z, A, B, a, and the dashedline are defined above, L is a halogen leaving group such as Br or I, L′is F or Cl, R is —(C₁-C₄)alkyl or —CF₃, R′ is —(C₁-C₄)alkyl, and u isthe integer 1 or 2.

Compounds of formula A1 and A2 are commercially available or can beprepared by methods known to the art.

A piperidinium salt of structure A1 can be reacted with a primary aminein a suitable solvent such as ethanol under reflux conditions in thepresence of a base such as potassium carbonate as described in reference“Lit 1” to provide the 1-(substituted)piperidine-4-one compound A3. Asdescribed in reference “Lit 2,” compound A3 can also be prepared byalkylation of a piperidine-4-one of structure A2 with an alkyl bromideor alkyl iodide in a suitable solvent such as dimethyl formamide,acetonitrile or dimethyl sulfoxide in the presence of an inorganic basesuch as potassium carbonate or an organic base such asdiisopropylethylamine. As described in reference “Lit 2,” compound A3can also be prepared by reductive amination of compound A2 with analdehyde or ketone using either sodium triacetoxyborohydride or sodiumcyanoborohydride in a suitable solvent such as dichloromethane ormethanol, respectively. Compound A3 can then be reductively aminatedwith a substituted or unsubstituted 1,2-phenylenediamine using sodiumtriacetoxyborohydride or sodium cyanoborohydride in a suitable solventsuch as dichloromethane or methanol, respectively, to provide compoundA4, as described in reference “Lit 2.” Compound A4 can be dissolved in asuitable solvent such as toluene and reacted with ethyl2-chloro-2-oxoacetate in the presence of a base such as triethylaminefollowed by treatment with an alkali metal alkoxide such as sodiumethoxide in a suitable solvent such as methanol or ethanol to providecompound A5. Compound A5 can be dissolved in a suitable solvent such astoluene and, as described in reference “Lit 3,” reacted with a group Vor VI halogenating agent, such as thionyl chloride, phosphorusoxychloride or phosphorus pentachloride, and a base such asdiisopropylethylamine in which an intermediate, believed to comprise a3-chloroquinoxalin-2-one, is formed then reacted with the desired amine,e.g., HNT₁T₂, to give compound A6, as shown in Scheme A.

As described in reference “Lit 1b,” compound A3 can be reacted with 50%aqueous hydroxylamine in a suitable solvent such as hexanes to providean intermediate hydroxylamine which can be converted to an oxime bydehydration in a suitable solvent such as toluene under refluxconditions using a Dean-Stark apparatus. The oxime intermediate can bereduced to the primary amine compound B1 by catalytic hydrogenationusing a catalyst such as rhodium on alumina in a suitable solvent suchas ethanol under a hydrogen atmosphere at a pressure of 1 atm or greaterin a suitable apparatus such as a Parr Hydrogenator according toreference “Lit 1b.” Compound B1 can be reacted with ethyl2-chloro-2-oxoacetate in the presence of a base such as triethylamine toprovide compound B2. Compound B2 can be reacted with a substituted orunsubstituted 2-halo-1-nitrobenzene (where the halo is fluoride orchloride) in the presence of a base such as potassium carbonate in asuitable solvent such as acetonitrile under reflux conditions to providecompound B3. Compound B3 can be treated with a hydrogenation catalystsuch as Raney nickel in a suitable solvent such as ethanol under ahydrogen atmosphere, and the product immediately treated with an alkalimetal alkoxide such as sodium ethoxide in a suitable solvent such asmethanol or ethanol to provide compound A5, which can be converted tocompound A6 as described in Scheme A.

The compound of formula C1 is commercially available or can be preparedby methods known to the art. Compound C1 can be reacted with an acidchloride RCOCl, such as 2,2,2-trifluoroacetyl chloride, or anhydride(RCO)₂O, such as 2,2,2-trifluoroacetic anhydride, and a base such astriethylamine in a suitable solvent such as dichloromethane ortetrahydrofuran to provide compound C2. Compound C2 can be converted tocompound C3 in a two step procedure by hydrolysis of the ester to thecarboxylic acid using an appropriate base such as aqueous NaOH, followedby treatment with diphenyl phosphorazidate (“(PhO)₂P(═O)N₃”) andphenylmethanol (“BnOH”) under Curtius rearrangement conditions. Thebenzyloxycarbonyl group of compound C3 can then be removed underhydrogenolysis conditions using a noble metal catalyst, e.g., palladiumon carbon, under a hydrogen atmosphere, to provide compound C4. CompoundC4 can be reacted with a substituted or unsubstituted2-halo-1-nitrobenzene (where the halo is fluoride or chloride) (similarto steps described in Scheme B) to provide compound C5. In the nextstep, compound C5 can be converted to compound C6 using a catalyst suchas Raney nickel in a suitable solvent such as ethanol under a hydrogenatmosphere as described in reference “Lit 4.” Compound C5 can also beconverted to compound C6 by chemical means, such as with Zn, Sn(II)chloride or Fe, or using sulfides or polysulfides by the Zinin Reductionas described in reference “Lit 5.” Compound C6 can then be treated withethyl 2-chloro-2-oxoacetate and a base such as triethylamine in asuitable solvent such as toluene, followed by treatment with an alkalimetal alkoxide such as sodium ethoxide in a suitable solvent such asethanol to provide compound C7. Compound A5 can be prepared byalkylation of compound C7 with an alkyl bromide or alkyl iodide or byreductive amination of compound C7 with an aldehyde or ketone, each asdescribed in Scheme A. Thereafter, compound A5 can be converted tocompound A6 as described in Scheme A.

The compound of formula D1 is commercially available or can be preparedfrom compound C1 by methods known to the art. Compound D2 can beprepared from compound D1 in a similar manner to the preparation ofcompound C4 from compound C1 in Scheme C. Compound D2 can be reactedwith a substituted or unsubstituted 2-halo-1-nitrobenzene (where thehalo is fluoride or chloride) (similar to steps described in Scheme B)to provide compound D3. In the next step (similar to steps described inScheme B), compound D3 can be converted to compound D4 by treatment witha hydrogenation catalyst such as Raney nickel in a suitable solvent suchas ethanol under a hydrogen atmosphere, or by chemical means using areducing agent such as Zn, Sn(II) chloride or Fe, or using sulfide orpolysulfides by the Zinin Reduction as described in Scheme C. Thereafter(similar to steps described in Scheme A), compound D4 can be treatedwith ethyl 2-chloro-2-oxoacetate in the presence of a base such astriethylamine followed by treatment with an alkali metal alkoxide suchas sodium ethoxide in a suitable solvent such as ethanol to providecompound D5. Compound D5 can be hydrogenolyzed using a noble metalcatalyst, e.g., palladium on carbon, in a suitable solvent such asmethanol or ethanol under a hydrogen atmosphere to provide compound C7.Compound A5 can be prepared by alkylation of compound C7 with an alkylbromide or alkyl iodide or by reductive amination of compound C7 with analdehyde or ketone (similar to steps described in Scheme A). Thereafter,compound A5 can be converted to compound A6 as described in Scheme A.

Compound E1, comprising a quinoxaline-2,3(1H,4H)-dithione, can be madeby, e.g., reacting Compound A5 (i.e., comprising aquinoxaline-2,3(1H,4H)-dione) with Lawesson's reagent (i.e.,2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)according to the procedure described in reference “Lit 6.” In oneembodiment, Compound E1 can be made by reacting Compound A5 withLawesson's reagent in a nonpolar solvent such as THF or toluene at atemperature of about 100° C. for about 2-3 hours, as shown above.Thereafter, compound E2 can be obtained from compound E1 in an analogousmanner as described in Scheme A for obtaining compound A6 from compoundA5 except that methyl iodide is used in place of thionyl chloride.

Compound A4 and diethyl 2-oxomalonate can be dissolved in a solvent witha high boiling point, such as toluene or xylene, and heated under refluxconditions with azeotropic removal of water to provide compound F1.Compound F1 can be hydrolyzed to the carboxylic acid F2 by treatmentwith a base, such as aqueous NaOH, in a solvent under appropriateconditions, such as methanol or ethanol at a temperature from about 0°C. to about 25° C. Upon completion of hydrolysis, the reaction mixtureis neutralized, e.g., with dilute HCl, to provide compound F2. CompoundF2 can be converted to amide derivative F3 by treatment with a couplingagent, such as N-(3,3-dimethylaminopropyl)-N′-ethylcarbodiimide andtriethylamine, and the desired amine, e.g., HNT₁T₂ shown in the scheme,in a solvent, such as DMF, to provide compound F3, e.g., according tothe procedure described in reference “Lit 7.”

Compound G1 can be obtained by chlorinating compound A5, e.g., by addinga chlorinating agent, such as thionyl chloride, phosphorus oxychlorideor phosphorus pentachoride, to a mixture of compound A5, DMF, and a basesuch as triethylamine in a solvent with a high boiling point, such astoluene or xylene, under reflux conditions such as is described inreference “Lit 3.” Compound G1 can be converted to compound G2 byreacting the former with the desired alkoxide, e.g., a sodium alkoxide,in a solvent, such as tetrahydrofuran, DMF or an alcohol of thealkoxide, to provide compound G2. In a similar manner but with thedesired thioalkoxide, e.g., a sodium thioalkoxide, compound G1 can beconverted to compound G3, comprising a thioalkoxide, in a suitablesolvent to provide compound G3. Compound G3 can be oxidized to thesulfoxide (u=1) or sulfone (u=2) of compound G4 by reacting compound G3with an oxidizing agent, such as oxone, in a suitable solvent, e.g., asdescribed in K. S. Webb, “A Mild, Inexpensive, and Practical Oxidationof Sulfides,” Tetrahedron Let., 35(21):3457-3460 (1994).

The compound of formula H1, wherein substituent groups A and B togetherform a bridge, e.g., a two carbon bridge, is commercially available orcan be prepared by methods known to the art.

When substituent groups A and B together form a bridge, e.g., a twocarbon bridge, compound H1 can be converted to compound H2, the “endo”isomer, under reductive amination conditions using, e.g., ammoniumformate and a noble metal catalyst, e.g., palladium on carbon, in asolvent such as ethanol or methanol as described in reference “Lit 8.”Similarly, where substituent groups A and B together form a bridge,e.g., a two carbon bridge, compound H1 can be reacted with aqueoushydroxylamine in a solvent such as hexanes to form an intermediatehydroxylamine, which can be converted to its oxime by dehydration in asolvent with a high boiling point such as toluene, under Dean-starkconditions. The oxime intermediate can be converted to compound H3, the“exo” isomer, by reduction using, e.g., sodium in propanol as describedin reference “Lit 9.”

Substituted-Quinoxaline-Type Piperidine Compounds such as I6 and I7where substituent groups A and B together form a bridge, e.g., a twocarbon bridge, can be prepared as described in Scheme I. Compound H2(the “endo” isomer) or H3 (the “exo” isomer) (where substituent groups Aand B together form a bridge, e.g., a two carbon bridge) can beconverted to compound I1 by reaction with a substituted or unsubstituted2-halo-1-nitrobenzene (where the halo is fluoride or chloride) and abase such as potassium carbonate, in a suitable solvent such as DMF oracetonitrile at a temperature from about 20° C. to about 100° C.Compound I1 can be demethylated to give compound I2 using, e.g.,1-chloromethylchloroformate in a solvent such as 1,2-dichloroethane,followed by treatment with methanol as described in “Lit 10.” CompoundI2 can be converted to compound I3 (similar to steps described inreference “Lit 2” in Scheme A). Compound I3 can be converted to compoundI4 by hydrogenation using a catalyst under a hydrogen atmosphere or bychemical means using a reducing agent (similar to steps described inreferences “Lit 4” and “Lit 5” in Scheme C). Compound I4 can beconverted to compound I5 by reaction with diethyl 2-oxomalonate in asolvent with a high boiling point such as toluene or xylene under refluxconditions. Compound I5 can be converted to the carboxylic acidderivative I6 by hydrolysis using a base such as aqueous NaOH in asuitable solvent such as methanol or ethanol, followed by neutralizationusing an acid such as dilute HCl. Compound I6 can be converted tocompound I7 by reaction with a coupling agent (similar to stepsdescribed in reference “Lit 7” in Scheme F).

Substituted-Quinoxaline-Type Piperidine Compounds such as J3 wheresubstituent groups A and B together form a bridge, e.g., a two carbonbridge, can be prepared as described in Scheme J. Compound I4 (wheresubstituent groups A and B together form a bridge, e.g., a two carbonbridge, and Compound I4 may exist as either an “endo” isomer an “exo”isomer or a mixture of “endolexo” isomers) can be converted to compoundJ1, as shown in Scheme J, by reaction with ethyl 2-chloro-2-oxoacetateand a base such as triethylamine in a suitable solvent such asdichloromethane, followed by reaction with an alkali metal alkoxide,using the procedures described in Scheme A. These “endo” and “exo”isomers can be conveniently separated by flash column chromatography.Compound J1 can be converted to compound J3, through compound J2(similar to steps described previously in Scheme A).

Substituted-Quinoxaline-Type Piperidine Compounds such as K2, K3 and K4where substituent groups A and B together form a bridge, e.g., a twocarbon bridge, can be prepared as described in Scheme K. Compound I6(where substituent groups A and B together form a bridge, e.g., a twocarbon bridge, and Compound I6 may exist as either an “endo” isomer an“exo” isomer or a mixture of “endo/exo” isomers) can be converted tocompound K1, as shown in Scheme K, using diphenylphosporyl azide andt-butanol under Curtius Rearrangement Conditions (similar to stepsdescribed in Scheme C). The tert-butoxycarbonyl group in compound K1 canbe removed using acid conditions such as HCl in a solvent such asdioxane or ether to give compound K2 as the hydrochloride salt. CompoundK2 can be converted to compound K3 using an acid chloride R₇COCl and abase such as triethylamine in a suitable solvent such as dichloromethaneor DMF, or using a carboxylic acid R₇COOH, a coupling reagent such asN-(3,3-dimethylaminopropyl)-N′-ethylcarbodiimide, a base such astriethylamine in a suitable solvent such as DMF as described in theliterature references in Scheme F. Compound K2 can be converted tocompound K4 using an alkyl or aryl sulfonyl chloride such asmethanesulfonyl chloride or sulfonic acid anhydride such astrifluoromethylsulfonic anhydride, a base such as triethylamine, in asuitable solvent such as dichloromethane.

Compound I4 can be prepared, as shown in Scheme L, from compound A1(similar to steps described in Scheme A). Where substituent groups A andB of compound I4 form a bridge, e.g., a two carbon bridge, the twoisomers, “exo” and “endo,” can be separated by chromatography and can beseparately converted to compounds such as A5, A6, F2, F3, and the likeas described earlier in Schemes A, B, and F.

As shown in Scheme M, compound A3 can be converted to compound M1 underreductive amination conditions using a BOC protected, substituted orunsubstituted 1,2-phenylenediamine and a reducing agent such as sodiumtriacetoxyborohydride or sodium cyanoborohydride in a suitable solventsuch as dichloromethane or methanol respectively as described inreference “Lit 2.” The BOC protecting group can be removed using acidicconditions, such as using HCl or 2,2,2-trifluoroacetic acid, to give anintermediate which can be converted to compound J1 in a two stepprocedure using ethyl 2-chloro-2-oxoacetate and a base such astriethylamine, followed by reaction with an alkali metal alkoxide suchas sodium ethoxide in a suitable solvent such as ethanol. Wheresubstituent groups A and B together form a bridge, e.g., a two carbonbridge, the “exo” and “endo” isomers which result can be convenientlyseparated using flash column chromatography.

Scheme N shows the conversion of the literature compound N1 tointermediates N8 and N9.

3-Oxo-8-aza-bicyclo[3.2.1]oct-6-ene-8-carboxylic acid methyl ester N1can be prepared according to the literature procedure described in N.Cramer; S. Laschat; A. Baro; W. Frey; Syn. Lett., (2003), 14, 2175-2177.

This intermediate N1 can be reacted with 1,2-phenylene-diamine underreductive amination conditions using sodium triacetoxyborohydride indichloromethane to give the coupled products3-(2-amino-phenylamino)-8-aza-bicyclo[3.2.1]oct-6-ene-8-carboxylic acidmethyl esters N2 and N3 as a mixture of endo and exo isomers which canbe taken to the next step without purification. Compounds N2 and N3 canbe dissolved in toluene and acetic acid to which diethyl ketomalonatecan be added and the mixture can be heated under reflux. Purification ofthe reaction mixture by column chromatography gives4-(8-methoxycarbonyl-8-aza-bicyclo[3.2.1]oct-6-en-3-yl-3-oxo-3,4-dihydro-quinoxaline-2-carboxylicacid ethyl esters N4 and N5 as a mixture of endo and exo esters whichcan be purified by chromatography. The methyl carbamate group can beremoved from N4 and N5 using iodo trimethylsilane in dichloromethane togive4-(8-aza-bicyclo[3.2.1]oct-6-en-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid ethyl esters N6 and N7 as a mixture of exo and endo isomers.Intermediates N6 and N7 can be alkylated with various alkyl bromides andiodides such as 3-bromo-cyclooctene and a catalytic amount of potassiumiodide and triethylamine in a solvent such as acetonitrile to giveisomers N8 and N9 which can be separated by column chromatography.Finally hydrolysis of the ester group can be achieved using sodiumhydroxide in aqueous ethanol to give the carboxylic acids N10 and N11 asshown in Scheme 0.

4.5 Therapeutic Uses of the Substituted-Quinoxaline-Type PiperidineCompounds

In accordance with the invention, the Substituted-Quinoxaline-TypePiperidine Compounds are administered to an animal in need of treatmentor prevention of a Condition.

In one embodiment, an effective amount of a Substituted-Quinoxaline-TypePiperidine Compound can be used to treat or prevent any conditiontreatable or preventable by inhibiting the activity of the ORL-1receptor. Examples of Conditions that are treatable or preventable byinhibiting the activity of the ORL-1 receptor include, but are notlimited to, pain (CNS effect), memory disorders, obesity, constipation,depression, dementia, and Parkinsonism.

In another embodiment, an effective amount of aSubstituted-Quinoxaline-Type Piperidine Compound can be used to treat orprevent any condition treatable or preventable by activating the ORL-1receptor. Examples of Conditions that are treatable or preventable byactivating the ORL-1 receptor include, but are not limited to, pain (PNSeffect), anxiety, cough, diarrhea, blood pressure disorder (viavasodilation and via diuresis), epilepsy, anorexia/cachexia, urinaryincontinence, and drug abuse.

The Substituted-Quinoxaline-Type Piperidine Compounds can be used totreat or prevent acute or chronic pain. Examples of pain that can betreated or prevented using a Substituted-Quinoxaline-Type PiperidineCompound include, but are not limited to, cancer pain, neuropathic pain,labor pain, myocardial infarction pain, pancreatic pain, colic pain,post-operative pain, headache pain, muscle pain, arthritic pain, andpain associated with a periodontal disease, including gingivitis andperiodontitis.

The Substituted-Quinoxaline-Type Piperidine Compounds can also be usedto treat or prevent pain associated with inflammation or with aninflammatory disease in an animal. Such pain can arise where there is aninflammation of the body tissue which can be a local inflammatoryresponse or a systemic inflammation. For example, aSubstituted-Quinoxaline-Type Piperidine Compound can be used to treat orprevent pain associated with inflammatory diseases including, but notlimited to, organ transplant rejection; reoxygenation injury resultingfrom organ transplantation (see Grupp et al., J. Mol, Cell Cardiol.31:297-303 (1999)) including, but not limited to, transplantation of theheart, lung, liver, or kidney; chronic inflammatory diseases of thejoints, including arthritis, rheumatoid arthritis, osteoarthritis andbone diseases associated with increased bone resorption; inflammatorybowel diseases, such as ileitis, ulcerative colitis, Barrett's syndrome,and Crohn's disease; inflammatory lung diseases, such as asthma, adultrespiratory distress syndrome, and chronic obstructive airway disease;inflammatory diseases of the eye, including corneal dystrophy, trachoma,onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis;chronic inflammatory disease of the gum, including gingivitis andperiodontitis; tuberculosis; leprosy; inflammatory diseases of thekidney, including uremic complications, glomerulonephritis andnephrosis; inflammatory disease of the skin, including sclerodermatitis,psoriasis and eczema; inflammatory diseases of the central nervoussystem, including chronic demyelinating diseases of the nervous system,multiple sclerosis, AIDS-related neurodegeneration and Alzheimer'sdisease, infectious meningitis, encephalomyelitis, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis and viral orautoimmune encephalitis; autoimmune diseases, including Type I and TypeII diabetes mellitus; diabetic complications, including, but not limitedto, diabetic cataract, glaucoma, retinopathy, nephropathy (such asmicroaluminuria and progressive diabetic nephropathy), gangrene of thefeet, atherosclerotic coronary arterial disease, peripheral arterialdisease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, jointproblems, and a skin or mucous membrane complication (such as aninfection, a shin spot, a candidal infection or necrobiosis lipoidicadiabeticorum), immune-complex vasculitis, and systemic lupuserythematosus (SLE); inflammatory disease of the heart, such ascardiomyopathy, ischemic heart disease hypercholesterolemia, andartherosclerosis; as well as various other diseases that can havesignificant inflammatory components, including preeclampsia, chronicliver failure, brain and spinal cord trauma, and cancer. ASubstituted-Quinoxaline-Type Piperidine Compound can also be used totreat or prevent pain associated with inflammatory disease that can, forexample, be a systemic inflammation of the body, exemplified bygram-positive or gram negative shock, hemorrhagic or anaphylactic shock,or shock induced by cancer chemotherapy in response to pro-inflammatorycytokines, e.g., shock associated with pro-inflammatory cytokines. Suchshock can be induced, e.g., by a chemotherapeutic agent that isadministered as a treatment for cancer.

The Substituted-Quinoxaline-Type Piperidine Compounds can also be usedto treat or prevent pain associated with nerve injury (i.e., neuropathicpain). Chronic neuropathic pain is a heterogenous disease state with anunclear etiology. In chronic neuropathic pain, the pain can be mediatedby multiple mechanisms. This type of pain generally arises from injuryto the peripheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. The chronic pain is differentfrom acute pain in that chronic neuropathic pain patients suffer theabnormal pain sensations that can be described as spontaneous pain,continuous superficial burning and/or deep aching pain. The pain can beevoked by heat-, cold-, and mechano-hyperalgesia, or by heat-, cold-, ormechano-allodynia.

Chronic neuropathic pain can be caused by injury or infection ofperipheral sensory nerves. It includes, but is not limited to, pain fromperipheral nerve trauma, herpes virus infection, diabetes mellitus,causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis.Neuropathic pain can also be caused by nerve damage from chronicalcoholism, human immunodeficiency virus infection, hypothyroidism,uremia, or vitamin deficiencies. Stroke (spinal or brain) and spinalcord injury can also induce neuropathic pain. Cancer-related neuropathicpain results from tumor growth compression of adjacent nerves, brain, orspinal cord. In addition, cancer treatments, including chemotherapy andradiation therapy, can cause nerve injury. Neuropathic pain includes butis not limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

The Substituted-Quinoxaline-Type Piperidine Compounds can be used totreat or prevent a migraine including, but not limited to, migrainewithout aura (“common migraine”), migraine with aura (“classicmigraine”), migraine without headache, basilar migraine, familialhemiplegic migraine, migrainous infarction, and migraine with prolongedaura.

According to the invention, some of the Substituted-Quinoxaline-TypePiperidine Compounds are agonists at the ORL-1 receptor, some of theSubstituted-Quinoxaline-Type Piperidine Compounds are partial agonistsat the ORL-1 receptor, and some of the Substituted-Quinoxaline-TypePiperidine Compounds are antagonists at the ORL-1 receptor. In anotherembodiment, a Substituted-Quinoxaline-Type Piperidine Compound is anagonist at the ORL-1 receptor and an agonist at a μ, κ and/or δ opioidreceptor, particularly at a μ opioid receptor. In another embodiment, aSubstituted-Quinoxaline-Type Piperidine Compound is a partial agonist atthe ORL-1 receptor and an agonist at a μ, κ and/or δ opioid receptor,particularly at a μ opioid receptor. In another embodiment, aSubstituted-Quinoxaline-Type Piperidine Compound is an antagonist at theORL-1 receptor and an agonist at a μ, κ and/or δ opioid receptor,particularly at a μ opioid receptor. In another embodiment, aSubstituted-Quinoxaline-Type Piperidine Compound is an agonist at theORL-1 receptor and an antagonist at a μ, κ and/or δ opioid receptor,particularly at a μ opioid receptor. In another embodiment, aSubstituted-Quinoxaline-Type Piperidine Compound is a partial agonist atthe ORL-1 receptor and an antagonist at a μ, κ and/or δ opioid receptor,particularly at a μ opioid receptor. In another embodiment, aSubstituted-Quinoxaline-Type Piperidine Compound is an antagonist at theORL-1 receptor and an antagonist at a μ, κ and/or δ opioid receptor,particularly at a μ opioid receptor.

The invention also provides methods for inhibiting ORL-1 receptorfunction in a cell, comprising contacting a cell capable of expressingthe ORL-1 receptor with an amount of a Substituted-Quinoxaline-TypePiperidine Compound effective to inhibit ORL-1 receptor function in thecell. This method can be adapted for use in vitro as part of an assay toselect compounds that can be useful for treating or preventing aCondition in an animal. Alternatively, this method can be adapted foruse in vivo, (i.e., in an animal such as a human) by contacting a cellin the animal with an effective amount of a Substituted-Quinoxaline-TypePiperidine Compound. In one embodiment, the method is useful fortreating or preventing pain in an animal in need of such treatment orprevention. In another embodiment, the method is useful for treating orpreventing a memory disorder, obesity, constipation, depression,dementia, or Parkinsonism in an animal in need of such treatment orprevention.

The invention also relates to methods for activating ORL-1 receptorfunction in a cell, comprising contacting a cell capable of expressingthe ORL-1 receptor with an amount of a Substituted-Quinoxaline-TypePiperidine Compound effective to activate ORL-1 receptor function in thecell. This method can be adapted for use in vitro as part of an assay toselect compounds useful for treating or preventing, pain, anxiety,cough, diarrhea, high blood pressure, epilepsy, anorexia/cachexia,urinary incontinence, or drug abuse. Alternatively, the method can beadapted for use in vivo (i.e., in an animal such as a human), bycontacting a cell in the animal with an effective amount of aSubstituted-Quinoxaline-Type Piperidine Compound. In one embodiment themethod is useful for treating or preventing pain in an animal in need ofsuch treatment or prevention. In another embodiment, the method isuseful for treating or preventing anxiety, cough, diarrhea, high bloodpressure, epilepsy, anorexia/chachexia, urinary incontinence, or drugabuse in an animal in need of such treatment or prevention.

Examples of tissue comprising cells capable of expressing the ORL-1receptor include but are not limited to brain, spinal cord, vasdeferens, and gastrointestinal tract tissue. Methods for assaying cellsthat express the ORL-1 receptor are known in the art; for example, seeY. Shimohigashi et al., “Sensitivity of opioid receptor-like receptorORL1 for chemical modification on nociceptin, a naturally occurringnociceptive peptide,” J. Biol. Chem. 271(39):23642-23645 (1996); M.Narita et al., “Identification of the G-protein coupled ORL1 receptor inthe mouse spinal cord by [³⁵S]-GTPγS binding and immunohistochemistry,”Brit. J. Pharmacol. 128:1300-1306 (1999); G. Milligan, “Principles:Extending then utility of [³⁵S]GTPγS binding assays,” TIPS 14:110-112(2003): and S. Lazareno, “Measurement of agonist-stimulated [³⁵S]GTPγSbinding to cell membranes,” Methods in Molecular Biology Vol. 106:231245(1999).

4.6 Therapeutic/Prophylactic Administration and Compositions of theInvention

Due to their activity, the Substituted-Quinoxaline-Type PiperidineCompounds are advantageously useful in human and veterinary medicine. Asdescribed above, the Substituted-Quinoxaline-Type Piperidine Compoundsare useful for treating or preventing a Condition in an animal in needthereof. The Substituted-Quinoxaline-Type Piperidine Compounds of theinvention can be administered to any animal requiring modulation of theopioid and/or ORL-1 receptors.

When administered to an animal, a Substituted-Quinoxaline-TypePiperidine Compound can be administered as a component of a compositionthat comprises a pharmaceutically acceptable carrier or excipient. Theinvention compositions, which comprise a Substituted-Quinoxaline-TypePiperidine Compound, can be administered orally. ASubstituted-Quinoxaline-Type Piperidine Compound can also beadministered by any other convenient route, for example, by infusion orbolus injection, by absorption through epithelial or mucocutaneouslinings (e.g., oral, rectal, and intestinal mucosa, etc.) and can beadministered together with a second therapeutically active agent.Administration can be systemic or local. Various delivery systems areknown, e.g., encapsulation in liposomes, microparticles, microcapsules,multiparticulates, capsules, etc., and can be used to administer aSubstituted-Quinoxaline-Type Piperidine Compound.

Methods of administration include, but are not limited to, intradermal,intramuscular, intraperitoneal, parenteral, intravenous, subcutaneous,intranasal, epidural, oral, sublingual, intracerebral, intravaginal,transdermal, rectal, by inhalation, or topical, particularly to theears, nose, eyes, or skin. The method of administration is left to thediscretion of the practitioner. In most instances, administration willresult in the release of a Substituted-Quinoxaline-Type PiperidineCompound into the bloodstream.

In specific embodiments, it can be desirable to administer aSubstituted-Quinoxaline-Type Piperidine Compound locally. This can beachieved, for example and not by way of limitation, by local infusionduring surgery, topical application, e.g., in conjunction with a wounddressing after surgery, by injection, by means of a catheter, by meansof a suppository or enema, or by means of an implant, said implant beingof a porous, non-porous, or gelatinous material, including membranes,such as sialastic membranes, or fibers.

In certain embodiments, it can be desirable to introduce aSubstituted-Quinoxaline-Type Piperidine Compound into the centralnervous system or gastrointestinal tract by any suitable route,including intraventricular, intrathecal, and epidural injection, andenema. Intraventricular injection can be facilitated by anintraventricular catheter, for example, attached to a reservoir, such asan Ommaya reservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, a Substituted-Quinoxaline-Type Piperidine Compoundcan be formulated as a suppository, with traditional binders andexcipients such as triglycerides.

When a Substituted-Quinoxaline-Type Piperidine Compound of the inventionis incorporated for parenteral administration by injection (e.g.,continuous infusion or bolus injection), the formulation for parenteraladministration can be in the form of a suspension, solution, emulsion inan oily or aqueous vehicle, and such formulations can further comprisepharmaceutically necessary additives such as one or more stabilizingagents, suspending agents, dispersing agents, and the like. ASubstituted-Quinoxaline-Type Piperidine Compound of the invention canalso be in the form of a powder for reconstitution as an injectableformulation.

In another embodiment, a Substituted-Quinoxaline-Type PiperidineCompound can be delivered in a vesicle, in particular a liposome (seeLanger, Science 249:1527-1533 (1990); and Treat et al., Liposomes in theTherapy of Infectious Disease and Cancer 317-327 and 353-365 (1989)).

In yet another embodiment, a Substituted-Quinoxaline-Type PiperidineCompound can be delivered in a controlled-release system orsustained-release system (see, e.g., Goodson, “Dental Applications” (pp.115-138) in Medical Applications of Controlled Release, Vol. 2,Applications and Evaluation, R. S. Langer and D. L. Wise eds., CRC Press(1984)). Other controlled- or sustained-release systems discussed in thereview by Langer, Science 249:1527-1533 (1990) can be used. In oneembodiment, a pump can be used (Langer, Science 249:1527-1533 (1990);Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al.,Surgery 88:507 (1980); and Saudek et al., N Engl. J. Med. 321:574(1989)). In another embodiment, polymeric materials can be used (seeMedical Applications of Controlled Release (Langer and Wise eds., 1974);Controlled Drug Bioavailability, Drug Product Design and Performance(Smolen and Ball eds., 1984); Ranger and Peppas, J. Macromol. Sci. Rev.Macromol. Chem. 23:61 (1983); Levy et al., Science 228:190 (1985);During et al., Ann. Neurol. 25:351 (1989); and Howard et al., J.Neurosurg. 71:105 (1989)). In yet another embodiment, a controlled- orsustained-release system can be placed in proximity of a target of aSubstituted-Quinoxaline-Type Piperidine Compound, e.g., the spinalcolumn, brain, or gastrointestinal tract, thus requiring only a fractionof the systemic dose.

The invention compositions can optionally comprise a suitable amount ofa pharmaceutically acceptable excipient so as to provide the form forproper administration to the animal. Such a pharmaceutical excipient canbe a diluent, suspending agent, solubilizer, binder, disintegrant,preservative, coloring agent, lubricant, and the like. Thepharmaceutical excipient can be a liquid, such as water or an oil,including those of petroleum, animal, vegetable, or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.The pharmaceutical excipient can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea, and the like. In addition,auxiliary, stabilizing, thickening, lubricating, and coloring agents canbe used. In one embodiment, the pharmaceutically acceptable excipient issterile when administered to an animal. Water is a particularly usefulexcipient when a Substituted-Quinoxaline-Type Piperidine Compound isadministered intravenously. Saline solutions and aqueous dextrose andglycerol solutions can also be employed as liquid excipients,particularly for injectable solutions. Suitable pharmaceuticalexcipients also include starch, glucose, lactose, sucrose, gelatin,malt, rice, flour, chalk, silica gel, sodium stearate, glycerolmonostearate, talc, sodium chloride, dried skim milk, glycerol,propylene glycol, water, ethanol, and the like. The inventioncompositions, if desired, can also contain minor amounts of wetting oremulsifying agents, or pH buffering agents. Specific examples ofpharmaceutically acceptable carriers and excipients that can be used toformulate oral dosage forms are described in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (1986).

The invention compositions can take the form of solutions, suspensions,emulsions, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the composition is in the form of a capsule(see, e.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical excipients are described in Remington's PharmaceuticalSciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporatedherein by reference.

In one embodiment, the Substituted-Quinoxaline-Type Piperidine Compoundsare formulated in accordance with routine procedures as a compositionadapted for oral administration to human beings. ASubstituted-Quinoxaline-Type Piperidine Compound to be orally deliveredcan be in the form of tablets, capsules, gelcaps, caplets, lozenges,aqueous or oily solutions, suspensions, granules, powders, emulsions,syrups, or elixirs, for example. When a Substituted-Quinoxaline-TypePiperidine Compound is incorporated into oral tablets, such tablets canbe compressed, tablet triturates, enteric-coated, sugar-coated,film-coated, multiply compressed or multiply layered. Techniques andcompositions for making solid oral dosage forms are described inPharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz,eds., 2nd ed.) published by Marcel Dekker, Inc. Techniques andcompositions for making tablets (compressed and molded), capsules (hardand soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences 1553-1593 (Arthur Osol, ed., 16^(th) ed., MackPublishing, Easton, Pa. 1980).

Liquid oral dosage forms include aqueous and nonaqueous solutions,emulsions, suspensions, and solutions and/or suspensions reconstitutedfrom non-effervescent granules, optionally containing one or moresuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, coloring agents, flavoring agents, and the like.Techniques and composition for making liquid oral dosage forms aredescribed in Pharmaceutical Dosage Forms: Disperse Systems, (Lieberman,Rieger and Banker, eds.) published by Marcel Dekker, Inc.

When a Substituted-Quinoxaline-Type Piperidine Compound is to beinjected parenterally, it can be, e.g., in the form of an isotonicsterile solution. Alternatively, when a Substituted-Quinoxaline-TypePiperidine Compound is to be inhaled, it can be formulated into a dryaerosol or can be formulated into an aqueous or partially aqueoussolution.

An orally administered Substituted-Quinoxaline-Type Piperidine Compoundcan contain one or more agents, for example, sweetening agents such asfructose, aspartame or saccharin; flavoring agents such as peppermint,oil of wintergreen, or cherry; coloring agents; and preserving agents,to provide a pharmaceutically palatable preparation. Moreover, where intablet or pill form, the compositions can be coated to delaydisintegration and absorption in the gastrointestinal tract therebyproviding a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compositions.In these latter platforms, fluid from the environment surrounding thecapsule is imbibed by the driving compound, which swells to displace theagent or agent composition through an aperture. These delivery platformscan provide an essentially zero order delivery profile as opposed to thespiked profiles of immediate release formulations. A time-delay materialsuch as glycerol monostearate or glycerol stearate can also be used.Oral compositions can include standard excipients such as mannitol,lactose, starch, magnesium stearate, sodium saccharin, cellulose, andmagnesium carbonate. In one embodiment, the excipients are ofpharmaceutical grade.

In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds can be formulated for intravenous administration. Typically,compositions for intravenous administration comprise sterile isotonicaqueous buffer. Where necessary, the compositions can also include asolubilizing agent. A Substituted-Quinoxaline-Type Piperidine Compoundfor intravenous administration can optionally include a local anestheticsuch as benzocaine or prilocaine to lessen pain at the site of theinjection. Generally, the ingredients are supplied either separately ormixed together in unit dosage form, for example, as a dry lyophilizedpowder or water free concentrate in a hermetically sealed container suchas an ampule or sachette indicating the quantity of active agent. Wherea Substituted-Quinoxaline-Type Piperidine Compound is to be administeredby infusion, it can be dispensed, for example, with an infusion bottlecontaining sterile pharmaceutical grade water or saline. Where aSubstituted-Quinoxaline-Type Piperidine Compound is administered byinjection, an ampule of sterile water for injection or saline can beprovided so that the ingredients can be mixed prior to administration.

A Substituted-Quinoxaline-Type Piperidine Compound can be administeredby controlled-release or sustained-release means or by delivery devicesthat are known to those in the art. Examples include, but are notlimited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767;5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of whichis incorporated herein by reference. Such dosage forms can be used toprovide controlled- or sustained-release of one or more activeingredients using, for example, hydropropylmethyl cellulose, otherpolymer matrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, multiparticulates, liposomes, microspheres, ora combination thereof to provide the desired release profile in varyingproportions. Suitable controlled- or sustained-release formulationsknown to those in the art, including those described herein, can bereadily selected for use with the active ingredients of the invention.The invention thus encompasses single unit dosage forms suitable fororal administration such as, but not limited to, tablets, capsules,gelcaps, and caplets that are adapted for controlled- orsustained-release.

Controlled- or sustained-release pharmaceutical compositions can have acommon goal of improving drug therapy over that achieved by theirnon-controlled or non-sustained-release counterparts. In one embodiment,a controlled- or sustained-release composition comprises a minimalamount of a Substituted-Quinoxaline-Type Piperidine Compound to treat orprevent the Condition or a symptom thereof in a minimum amount of time.Advantages of controlled- or sustained-release compositions includeextended activity of the drug, reduced dosage frequency, and increasedcompliance. In addition, controlled- or sustained-release compositionscan favorably affect the time of onset of action or othercharacteristics, such as blood levels of theSubstituted-Quinoxaline-Type Piperidine Compound, and can thus reducethe occurrence of adverse side effects.

Controlled- or sustained-release compositions can initially release anamount of a Substituted-Quinoxaline-Type Piperidine Compound thatpromptly produces the desired therapeutic or prophylactic effect, andgradually and continually release other amounts of theSubstituted-Quinoxaline-Type Piperidine Compound to maintain this levelof therapeutic or prophylactic effect over an extended period of time.To maintain a constant level of the Substituted-Quinoxaline-TypePiperidine Compound in the body, the Substituted-Quinoxaline-TypePiperidine Compound can be released from the dosage form at a rate thatwill replace the amount of Substituted-Quinoxaline-Type PiperidineCompound being metabolized and excreted from the body. Controlled- orsustained-release of an active ingredient can be stimulated by variousconditions, including but not limited to, changes in pH, changes intemperature, concentration or availability of enzymes, concentration oravailability of water, or other physiological conditions or compounds.

The amount of the Substituted-Quinoxaline-Type Piperidine Compound thatis effective for the treatment or prevention of a Condition can bedetermined by standard clinical techniques. In addition, in vitro and/orin vivo assays can optionally be employed to help identify optimaldosage ranges. The precise dose to be employed will also depend on,e.g., the route of administration and the seriousness of the Condition,and can be decided according to the judgment of a practitioner and/oreach animal's circumstances. In other examples thereof, variations willnecessarily occur depending upon the weight and physical condition(e.g., hepatic and renal function) of the animal being treated, theaffliction to be treated, the severity of the symptoms, the frequency ofthe dosage interval, the presence of any deleterious side-effects, andthe particular compound utilized, among other things.

Suitable effective dosage amounts, however, range from about 0.01 mg/kgof body weight to about 3000 mg/kg of body weight of the animal per day,although they are typically from about 0.01 mg/kg of body weight toabout 2500 mg/kg of body weight of the animal per day or from about 0.01mg/kg of body weight to about 1000 mg/kg of body weight of the animalper day. In one embodiment, the effective dosage amount is about 100mg/kg of body weight of the animal per day or less. In anotherembodiment, the effective dosage amount ranges from about 0.01 mg/kg ofbody weight to about 100 mg/kg of body weight of the animal per day of aSubstituted-Quinoxaline-Type Piperidine Compound, in another embodiment,about 0.02 mg/kg of body weight to about 50 mg/kg of body weight of theanimal per day, and in another embodiment, about 0.025 mg/kg of bodyweight to about 20 mg/kg of body weight of the animal per day.

Administration can be as a single dose or as a divided dose. In oneembodiment, an effective dosage amount is administered about every 24 hruntil the Condition is abated. In another embodiment, an effectivedosage amount is administered about every 12 hr until the Condition isabated. In another embodiment, an effective dosage amount isadministered about every 8 hr until the Condition is abated. In anotherembodiment, an effective dosage amount is administered about every 6 hruntil the Condition is abated. In another embodiment, an effectivedosage amount is administered about every 4 hr until the Condition isabated. The effective dosage amounts described herein refer to totalamounts administered; that is, if more than oneSubstituted-Quinoxaline-Type Piperidine Compound is administered, theeffective dosage amounts correspond to the total amount administered.

Where a cell capable of expressing the ORL-1 receptor, the μ-opioidreceptor, the κ-opioid receptor and/or the δ-opioid receptor iscontacted with a Substituted-Quinoxaline-Type Piperidine Compound invitro, the amount effective for inhibiting or activating that receptorfunction in a cell will typically range from about 10⁻¹² mol/L to about10⁻⁴ mol/L, in one embodiment, from about 10⁻¹² mol/L to about 10⁻⁵mol/L, in another embodiment, from about 10⁻¹² mol/L to about 10⁻⁶mol/L, and in another embodiment, from about 10⁻¹² mol/L to about 10⁻⁹mol/L of a solution or suspension of a pharmaceutically acceptablecarrier or excipient. In one embodiment, the volume of solution orsuspension comprising the Substituted-Quinoxaline-Type PiperidineCompound will be from about 0.01 μL to about 1 mL. In anotherembodiment, the volume of solution or suspension will be about 200 μL.

The Substituted-Quinoxaline-Type Piperidine Compounds will have abinding affinity (K_(i)) for the human ORL-1 receptor of about 1000 nMor less in one embodiment, or about 500 nM or less in anotherembodiment, about 100 nM or less in another embodiment, about 50 nM orless in another embodiment, or about 20 nM or less in anotherembodiment, or about 5 nM or less in another embodiment. The bindingaffinity K_(i) can be measured in ways known to the art, e.g., by anassay utilizing membranes from recombinant HEK-293 cells expressing theORL-1 receptor.

Typically, the Substituted-Quinoxaline-Type Piperidine Compounds willhave a Ki (nM) of about 300 or less for binding to ORL-1 receptors. Inone embodiment, the Substituted-Quinoxaline-Type Piperidine Compounds ofthe invention will have a Ki (nM) of about 100 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds of theinvention will have a Ki (nM) of about 35 or less. In anotherembodiment, the Substituted-Quinoxaline-Type. Piperidine Compounds ofthe invention will have a Ki (nM) of about 20 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds of theinvention will have a Ki (nM) of about 15 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds of theinvention will have a Ki (nM) of about 10 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds of theinvention will have a Ki (nM) of about 4 or less. In another embodiment,the Substituted-Quinoxaline-Type Piperidine Compounds of the inventionwill have a Ki (nM) of about 1 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave a Ki (nM) of about 0.4 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave a Ki (nM) of about 0.1 or less.

ORL-1 GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at an ORL-1 receptor.Substituted-Quinoxaline-Type Piperidine Compounds typically will have anORL-1 GTP EC₅₀ (nM) of about 5000 or less to stimulate ORL-1 receptorfunction. In one embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have an ORL-1 GTP EC₅₀ (nM) of about1000 or less. In another embodiment, the Substituted-Quinoxaline-TypePiperidine Compounds of the invention will have an ORL-1 GTP EC₅₀ (nM)of about 100 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave an ORL-1 GTP EC₅₀ (nM) of about 80 or less. In another embodiment,the Substituted-Quinoxaline-Type Piperidine Compounds of the inventionwill have an ORL-1 GTP EC₅₀ (nM) of about 50 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds of theinvention will have an ORL-1 GTP EC₅₀ (nM) of about 35 or less. Inanother embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have an ORL-1 GTP EC₅₀ (nM) of about 15or less. In another embodiment, the Substituted-Quinoxaline-TypePiperidine Compounds will have an ORL-1 GTP EC₅₀ (nM) of about 10 orless. In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds will have an ORL-1 GTP EC₅₀ (nM) of about 4 or less. Inanother embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds will have an ORL-1 GTP EC₅₀ (nM) of about 1 or less. Inanother embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds will have an ORL-1 GTP EC₅₀ (nM) of about 0.4 or less. Inanother embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds will have an ORL-1 GTP EC₅₀ (nM) of about 0.1 or less.

ORL-1 GTP Emax (%) is the maximal effect elicited by a compound relativeto the effect elicited by nociceptin, a standard ORL-1 agonist.Typically, a Substituted-Quinoxaline-Type Piperidine Compound of theinvention acting as an agonist will have an ORL-1 GTP Emax (%) of about50% or greater. In one embodiment, agonist Substituted-Quinoxaline-TypePiperidine Compounds will have an ORL-1 GTP Emax (%) of about 75% orgreater. In another embodiment, agonist Substituted-Quinoxaline-TypePiperidine Compounds will have an ORL-1 GTP Emax (%) of about 85% orgreater. In another embodiment, agonist Substituted-Quinoxaline-TypePiperidine Compounds will have an ORL-1 GTP Emax (%) of about 95% orgreater. In another embodiment, agonist Substituted-Quinoxaline-TypePiperidine Compounds will have an ORL-1 GTP Emax (%) of about 100% orgreater. Typically, a Substituted-Quinoxaline-Type Piperidine Compoundof the invention acting as a partial agonist will have an ORL-1 GTP Emax(%) of less than about 10%. In one embodiment, partial agonistSubstituted-Quinoxaline-Type Piperidine Compounds will have an ORL-1 GTPEmax (%) of less than about 20%. In another embodiment, partial agonistSubstituted-Quinoxaline-Type Piperidine Compounds will have an ORL-1 GTPEmax (%) of less than about 30%. In another embodiment, partial agonistSubstituted-Quinoxaline-Type Piperidine Compounds will have an ORL-1 GTPEmax (%) of less than about 40%. In another embodiment, partial agonistSubstituted-Quinoxaline-Type Piperidine Compounds will have an ORL-1 GTPEmax (%) of less than about 50%.

The Substituted-Quinoxaline-Type Piperidine Compounds will have abinding affinity (Ki) for the human g-opioid receptors of about 1000 nMor less in one embodiment, or about 500 nM or less in anotherembodiment, about 100 nM or less in another embodiment, about 50 nM orless in another embodiment, or about 20 nM or less in anotherembodiment, or about 5 nM or less in another embodiment.

Typically, the Substituted-Quinoxaline-Type Piperidine Compounds willhave a Ki (nM) of about 3000 or less for binding to g-opioid receptors.In one embodiment, the Substituted-Quinoxaline-Type Piperidine Compoundsof the invention will have a Ki (nM) of about 1000 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds of theinvention will have a Ki (nM) of about 650 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds of theinvention will have a Ki (nM) of about 525 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds of theinvention will have a Ki (nM) of about 250 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds of theinvention will have a Ki (nM) of about 100 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds of theinvention will have a Ki (nM) of about 10 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds of theinvention will have a Ki (nM) of about 1 or less.

μ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a μ-opioid receptor.Substituted-Quinoxaline-Type Piperidine Compounds typically will have aμ GTP EC₅₀ (nM) of about 5000 or less to stimulate μ-opioid receptorfunction. In one embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a g GTP EC₅₀ (nM) of about 4100 orless. In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a g GTP EC₅₀ (nM) of about 3100 orless. In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a μ GTP EC₅₀ (nM) of about 2000 orless. In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a μ GTP EC₅₀ (nM) of about 1000 orless. In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a μ GTP EC₅₀ (nM) of about 100 orless. In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds will have a μ GTP EC₅₀ (nM) of about 10 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds willhave a μ GTP EC₅₀ (nM) of about 1 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a μ GTP EC₅₀(nM) of about 0.4 or less.

μ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by DAMGO, a standard μ agonist. Typically, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave a μ GTP Emax (%) of about 10% or greater. In one embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a μ GTP Emax(%) of about 20% or greater. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a μ GTP Emax(%) of about 50% or greater. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a μ GTP Emax(%) of about 65% or greater. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a μ GTP Emax(%) of about 75% or greater. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a μ GTP Emax(%) of about 88% or greater.

Typically, the Substituted-Quinoxaline-Type Piperidine Compounds willhave a Ki (nM) of about 20,000 or less for κ receptors. In oneembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds willhave substantially no activity. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 10,000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 5000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 1000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 500 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 300 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 100 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 50 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 20 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 15 or less.

κ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a κ receptor.Substituted-Quinoxaline-Type Piperidine Compounds typically will have aκ GTP EC₅₀ (nM) of about 20,000 or less to stimulate κ opioid receptorfunction. In one embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds will have a κ GTP EC₅₀ (nM) of about 10,000 or less. Inanother embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds will have a κ GTP EC₅₀ (nM) of about 5000 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds willhave a κ GTP EC₅₀ (nM) of about 2000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 1500 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 800 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 500 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 300 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 100 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 50 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 25 or less.

κ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by U69,593. Typically, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave a κ GTP Emax (%) of about 10% or greater. In one embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP Emax(%) of about 15% or greater. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP Emax(%) of about 30% or greater. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP Emax(%) of about 40% or greater. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP Emax(%) of about 45% or greater. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP Emax(%) of about 75% or greater. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP Emax(%) of about 90% or greater.

Typically, the Substituted-Quinoxaline-Type Piperidine Compounds willhave a Ki (nM) of about 20,000 or less for δ receptors. In oneembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds willhave substantially no activity. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 10,000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 9000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 7500 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 6500 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 5000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 3000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 2500 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 1000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 500 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 350 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 250 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 100 or less.

δ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a δ receptor.Substituted-Quinoxaline-Type Piperidine Compounds typically will have aδ GTP EC₅₀ (nM) of about 20,000 or less to stimulate δ opioid receptorfunction. In one embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds will have a δ GTP EC₅₀ (nM) of about 10,000 or less. Inanother embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds will have a δ GTP EC₅₀ (nM) of about 1000 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds willhave a δ GTP EC₅₀ (nM) of about 100 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP EC₅₀(nM) of about 90 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP EC₅₀(nM) of about 50 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP EC₅₀(nM) of about 25 or less or less.

δ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by met-enkephalin. Typically, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave a δ GTP Emax (%) of about 10% or greater. In one embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP Emax(%) of about 30% or greater. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP Emax(%) of about 50% or greater. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP Emax(%) of about 75% or greater. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP Emax(%) of about 90% or greater. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP Emax(%) of about 100% or greater.

The Substituted-Quinoxaline-Type Piperidine Compounds can be assayed invitro or in vivo for the desired therapeutic or prophylactic activityprior to use in humans. Animal model systems can be used to demonstratesafety and efficacy.

The methods for treating or preventing a Condition in an animal in needthereof can further comprise co-administering to the animal beingadministered a Substituted-Quinoxaline-Type Piperidine Compound (i.e., afirst therapeutic agent) a second therapeutic agent. In one embodiment,the second therapeutic agent is administered in an effective amount.

An effective amount of the second therapeutic agent will be known tothose skilled the art depending on the agent. However, it is well withinthe skilled artisan's purview to determine the second therapeuticagent's optimal effective-amount range. A Substituted-Quinoxaline-TypePiperidine Compound and the second therapeutic agent combined can acteither additively or synergistically to treat the same Condition, orthey may act independently of each other such that theSubstituted-Quinoxaline-Type Piperidine Compound treats or prevents afirst Condition and the second therapeutic agent treats or prevents asecond disorder, which can be the same as the first Condition or anotherdisorder. In one embodiment of the invention, where a second therapeuticagent is administered to an animal for treatment of a Condition (e.g.,pain), the minimal effective amount of the Substituted-Quinoxaline-TypePiperidine Compound will be less than its minimal effective amount wouldbe where the second therapeutic agent is not administered. In thisembodiment, the Substituted-Quinoxaline-Type Piperidine Compound and thesecond therapeutic agent can act synergistically to treat or prevent aCondition. In one embodiment, a Substituted-Quinoxaline-Type PiperidineCompound is administered concurrently with a second therapeutic agent asa single composition comprising an effective amount of aSubstituted-Quinoxaline-Type Piperidine Compound and an effective amountof the second therapeutic agent. Alternatively, a composition comprisingan effective amount of a Substituted-Quinoxaline-Type PiperidineCompound and a second composition comprising an effective amount of thesecond therapeutic agent are concurrently administered. In anotherembodiment, an effective amount of a Substituted-Quinoxaline-TypePiperidine Compound is administered prior or subsequent toadministration of an effective amount of the second therapeutic agent.In this embodiment, the Substituted-Quinoxaline-Type Piperidine Compoundis administered while the second therapeutic agent exerts itstherapeutic effect, or the second therapeutic agent is administeredwhile the Substituted-Quinoxaline-Type Piperidine Compound exerts itstherapeutic effect for treating or preventing a Condition.

The second therapeutic agent can be, but is not limited to, an opioidagonist, a non-opioid analgesic, a non-steroidal anti-inflammatoryagent, an antimigraine agent, a Cox-II inhibitor, a 5-lipoxygenaseinhibitor, an anti-emetic, a β-adrenergic blocker, an anticonvulsant, anantidepressant, a Ca²⁺-channel blocker, an anti-cancer agent, an agentfor treating or preventing UI, an agent for treating or preventinganxiety, an agent for treating or preventing a memory disorder, an agentfor treating or preventing obesity, an agent for treating or preventingconstipation, an agent for treating or preventing cough, an agent fortreating or preventing diarrhea, an agent for treating or preventinghigh blood pressure, an agent for treating or preventing epilepsy, anagent for treating or preventing anorexia/cachexia, an agent fortreating or preventing drug abuse, an agent for treating or preventingan ulcer, an agent for treating or preventing IBD, an agent for treatingor preventing IBS, an agent for treating or preventing addictivedisorder, an agent for treating or preventing Parkinson's disease andparkinsonism, an agent for treating or preventing a stroke, an agent fortreating or preventing a seizure, an agent for treating or preventing apruritic condition, an agent for treating or preventing psychosis, anagent for treating or preventing Huntington's chorea, an agent fortreating or preventing ALS, an agent for treating or preventing acognitive disorder, an agent for treating or preventing a migraine, anagent for inhibiting vomiting, an agent for treating or preventingdyskinesia, an agent for treating or preventing depression, or anymixture thereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable derivatives thereof, or anymixture thereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable derivativesthereof, or any mixture thereof.

Examples of useful non-opioid analgesics include, but are not limitedto, non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen,diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen,ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen,muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid,fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac,tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac,mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid,tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam,a pharmaceutically acceptable derivative thereof, or any mixturethereof. Other suitable non-opioid analgesics include the following,non-limiting, chemical classes of analgesic, antipyretic, nonsteroidalanti-inflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophenol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);alkanones, including nabumetone; a pharmaceutically acceptablederivative thereof; or any mixture thereof. For a more detaileddescription of the NSAIDs, see Paul A. Insel, Analgesic-Antipyretic andAnti-inflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57 (P.B. Molinhoff and R. W. Ruddon eds., 9^(th) ed 1996), and G. R. Hanson,Analgesic, Antipyretic and Anti-Inflammatory Drugs in Remington: TheScience and Practice of Pharmacy Vol II 1196-1221 (A. R. Gennaro ed.19^(th) ed. 1995), which are hereby incorporated by reference in theirentireties.

Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox-II inhibitors include, but are not limited to, celecoxib,DUP-697, flosulide, meloxicam, 6-MNA, L-745337, rofecoxib, nabumetone,nimesulide, NS-398, SC-5766, T-614, L-768277, GR-253035, JTE-522,RS-57067-000, SC-58125, SC-078, PD-138387, NS-398, flosulide, D-1367,SC-5766, PD-164387, etoricoxib, valdecoxib, parecoxib, apharmaceutically acceptable derivative thereof, or any mixture thereof.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, a pharmaceutically acceptable derivative thereof, or anymixture thereof.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenytoin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin,zonisamide, a pharmaceutically acceptable derivative thereof, or anymixture thereof.

Examples of useful Ca²⁺-channel blockers include, but are not limitedto, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil,prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine,barnidipine, benidipine, cilnidipine, efonidipine, elgodipine,felodipine, isradipine, lacidipine, lercanidipine, manidipine,nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine,nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine,bencyclane, etafenone, fantofarone, perhexiline, a pharmaceuticallyacceptable derivative thereof, or any mixture thereof.

Examples of useful therapeutic agents for treating or preventing UIinclude, but are not limited to, propantheline, imipramine, hyoscyamine,oxybutynin, dicyclomine, a pharmaceutically acceptable derivativethereof, or any mixture thereof.

Examples of useful therapeutic agents for treating or preventing anxietyinclude, but are not limited to, benzodiazepines, such as alprazolam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam,lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam,quazepam, temazepam, and triazolam; non-benzodiazepine agents, such asbuspirone, gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, andzaleplon; tranquilizers, such as barbituates, e.g., amobarbital,aprobarbital, butabarbital, butalbital, mephobarbital, methohexital,pentobarbital, phenobarbital, secobarbital, and thiopental; propanediolcarbamates, such as meprobamate and tybamate; a pharmaceuticallyacceptable derivative thereof; or any mixture thereof.

Examples of useful therapeutic agents for treating or preventingdiarrhea include, but are not limited to, diphenoxylate, loperamide, apharmaceutically acceptable derivative thereof, or any mixture thereof.

Examples of useful therapeutic agents for treating or preventingepilepsy include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproicacid, trimethadione, benzodiazepines, γ vinyl GABA, acetazolamide,felbamate, a pharmaceutically acceptable derivative thereof, or anymixture thereof.

Examples of useful therapeutic agents for treating or preventing drugabuse include, but are not limited to, methadone, desipramine,amantadine, fluoxetine, buprenorphine, an opiate agonist,3-phenoxypyridine, levomethadyl acetate hydrochloride, serotoninantagonists, a pharmaceutically acceptable derivative thereof, or anymixture thereof.

Examples of non-steroidal anti-inflammatory agents, 5-lipoxygenaseinhibitors, anti-emetics, β-adrenergic blockers, antidepressants, andanti-cancer agents are known in the art and can be selected by thoseskilled in the art. Examples of useful therapeutic agents for treatingor preventing memory disorder, obesity, constipation, cough, high bloodpressure, anorexia/cachexia, an ulcer, IBD, IBS, addictive disorder,Parkinson's disease and parkinsonism, a stroke, a seizure, a pruriticcondition, psychosis, Huntington's chorea, ALS, a cognitive disorder, amigraine, dyskinesia, depression, and/or treating, preventing orinhibiting vomiting include those that are known in the art and can beselected by those skilled in the art.

A composition of the invention is prepared by a method comprisingadmixing a Substituted-Quinoxaline-Type Piperidine Compound or apharmaceutically acceptable derivative thereof with a pharmaceuticallyacceptable carrier or excipient. Admixing can be accomplished usingmethods known for admixing a compound (or derivative) and apharmaceutically acceptable carrier or excipient. In one embodiment, theSubstituted-Quinoxaline-Type Piperidine Compound is present in thecomposition in an effective amount.

4.7 Kits

The invention further provides kits that can simplify the handling andadministration of a Substituted-Quinoxaline-Type Piperidine Compound toan animal.

A typical kit of the invention comprises a unit dosage form of aSubstituted-Quinoxaline-Type Piperidine Compound. In one embodiment, theunit dosage form comprises a first container, which can be sterile,containing an effective amount of a Substituted-Quinoxaline-TypePiperidine Compound and a pharmaceutically acceptable carrier orexcipient. The kit can further comprise a label or printed instructionsinstructing the use of the Substituted-Quinoxaline-Type PiperidineCompound to treat or prevent a Condition. The kit can further comprise aunit dosage form of a second therapeutic agent, for example, a secondcontainer containing an effective amount of the second therapeutic agentand a pharmaceutically acceptable carrier or excipient. In anotherembodiment, the kit comprises a container containing an effective amountof a Substituted-Quinoxaline-Type Piperidine Compound, an effectiveamount of a second therapeutic agent and a pharmaceutically acceptablecarrier or excipient. Examples of second therapeutic agents include, butare not limited to, those listed above.

Kits of the invention can further comprise a device that is useful foradministering the unit dosage forms. Examples of such a device include,but are not limited to, a syringe, a drip bag, a patch, an inhaler, andan enema bag.

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, that would be within the purview of those skilled inthe art, and changes in formulation or changes in experimental design,are to be considered to fall within the scope of the inventionincorporated herein.

5. EXAMPLES

The following examples illustrate various aspects of the invention, andare not to be construed to limit the claims in any manner whatsoever.

5.1 Example 1

1-Cyclooctylpiperidin-4-one (compound of formula AA) was purchased fromVasudha Pharma Chem LTD (Hyderabad, Andhra Pradesh, India).

The compound of formula AA (10.00 g, 48.0 mmol) and 1,2-phenylenediamine(10.38 g, 96.0 mmol, Sigma-Aldrich, St. Louis, Mo.) were suspended in200 mL of CH₂Cl₂. To this mixture, sodium triacetoxyborohydride(NaBH(OAc)₃, 30.42 g, 144.0 mmol, Acros Organics, Geel, Belgium) andacetic acid (10 mL) were added. The reaction mixture was stirred at atemperature of about 25° C. for 24 hrs after which the reaction mixturewas extracted 10 times with about 200 mL of water each time. The organicportion was dried (MgSO₄), filtered, and concentrated to dryness underreduced pressure to provide 9.48 g of a compound of formula AB as alight orange oil (yield 65.6%).

The identity of the compound of formula AB,N¹-(1-cyclooctylpiperidin-4-yl)benzene-1,2-diamine, was confirmed usingliquid chromatography/mass spectrometry (LC/MS).

Compound AB: LC/MS (95%, t_(r)=1.832 min): m/z=301.1 [M+H]⁺ (Calc:302.2).

To a suspension of 199 mg (0.66 mmol) of the compound of formula AB andexcess NaHCO₃ in 10 mL of DCM at 0° C. was added di-tert-butyldicarbonate ((BOC)₂O, 144 mg, 0.66 mmol, Sigma-Aldrich). After theaddition, the reaction mixture was warmed to a temperature of about 25°C. and stirred for 2 hrs. The reaction mixture was then poured onto asilica gel column and eluted with 5%:95% MeOH:DCM to provide 247 mg ofthe compound of formula AC as light yellow solid (yield 93%).

The identity of the compound of formula AC, tert-butyl2-(1-cyclooctylpiperidin-4-ylamino)phenylcarbamate, was confirmed using¹H NMR.

Compound AC: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.24 (bs, 1H), 6.98 (dt,1H, J=1.5, 8 Hz), 6.67 (m, 2H), 6.12 (bs, 1H), 3.53 (bs, 1H), 3.13 (m,1H), 2.71 (m, 2H), 2.56 (m, 1H), 2.27 (t, 2H, J=10 Hz), 1.95 (m, 2H),1.70-1.35 (m, 15H), 1.43 (s, 9H).

To a suspension of 230 mg of the compound of formula AC and excess ofNaHCO₃ in DCM at 0° C. was added dropwise via a syringe 2-chloroacetylchloride (0.047 mL, 0.57 mmol, Sigma-Aldrich). After addition, thereaction mixture was warmed to a temperature of about 25° C. and stirredfor 30 min more. Thereafter, the reaction mixture was evaporated todryness under reduced pressure to provide 273 mg of the compound offormula AD (yield >98%).

The identity of the compound of formula AD, tert-butyl2-(2-chloro-N-(1-cyclooctylpiperidin-4-yl)acetamido)phenylcarbamate, wasconfirmed using mass spectrometry (MS).

Compound AD: MS: m/z=478 (M+1) (Calc: 477).

50 mg of the compound of formula AD was added to 3 mL of DMF at 0° C. Tothis mixture was added excess of NaH (3 equivalents, Sigma-Adrich).Thereafter, the reaction mixture was warmed to a temperature of about25° C. and stirred for 10 min. After cooling to 0° C., the reactionmixture was quenched by the addition of ice water. The reaction mixturewas diluted with EtOAc then washed twice with brine. The brine wasextracted with EtOAc. The organic portions were combined, dried(Na₂SO₄), filtered, and concentrated under reduced pressure to provide aresidue. The residue was chromatographed with a silica gel column elutedwith EtOAc to provide the compound of formula AE (yield >98%).

The identity of the compound of formula AE, tert-butyl4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxylate,was confirmed using ¹H NMR.

Compound AE: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.63 (bs, 1H), 7.34 (dd,1H, J=1.5, 8 Hz), 7.13 (dt, 1H, J=1.5, 8 Hz), 7.08 (dt, 1H, J=1.5, 8Hz), 4.29 (s, 2H), 4.29 (m, 1H), 2.92 (bd, 2H, J=10 Hz), 2.66 (m, 1H),2.54 (m, 2H), 2.36 (t, 2H, J=10 Hz), 1.80-1.43 (m, 16H), 1.54 (s, 9H).

The compound of formula AE was added to 4N HCl in 1,4-dioxane at atemperature of about 25° C. for 30 min then concentrated under reducedpressure to provide a residue. The residue was diluted with EtOAc andwashed with saturated aqueous NaHCO₃ solution. The organic portion wasdried (Na₂SO₄), filtered, and concentrated under reduced pressure toprovide a residue. The residue was then chromatographed by preparativeTLC (eluted with 15%:85% MeOH:DCM) to provide 31 mg of theSubstituted-Quinoxaline-Type Piperidine Compound of formula 85 (yield98%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 85,1-(1-cyclooctylpiperidin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one, wasconfirmed using ¹H NMR and MS.

Substituted-Quinoxaline-Type Piperidine Compound 85: ¹H NMR: δ_(H) (400MHz, CDCl₃): 12.21 (bs, 0.5H), 7.78 (m, 1H), 6.99 (m, 1H), 6.87 (t, 1H,J=8 Hz), 6.66 (d, 1H, J=8 Hz), 5.03 (bs, 1H), 3.79 (s, 2H), 3.71 (s,1H), 3.34 (m, 4H), 2.95 (m, 1H), 2.19 (m, 1H), 1.8-1.3 (m, 18H); MS:m/z=342 (M+1) (Calc: 341).

5.2 Example 2

190 mg (0.63 mmol) of the compound of formula AB was mixed with 7 mL ofDCM. NaHCO₃ (158 mg, 1.89 mmol) was added and the resulting suspensionwas stirred at 0° C. To the suspension was then added dropwise via asyringe 2-chloroacetyl chloride (0.051 mL, 0.63 mmol). After addition,the reaction mixture was warmed to a temperature of about 25° C. andstirred for 10 min. The reaction mixture was then evaporated to drynessunder reduced pressure, acetonitrile was added, and the resultingsuspension was heated at 80° C. for 48 hr. The suspension was pouredonto a silica gel column and eluted with 5%:95% MeOH:DCM to provide 168mg of Substituted-Quinoxaline-Type Piperidine Compound 86 as lightyellow solid (yield 78%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 86,4-(1-cyclooctylpiperidin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one, wasconfirmed using ¹H NMR and MS.

Substituted-Quinoxaline-Type Piperidine Compound 86: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.53 (bs, 1H), 6.93 (dt, 1H, J=1.5, 8 Hz), 6.69 (m, 2H),3.71 (s, 2H), 3.43 (m, 1H), 2.88 (m, 2H), 2.61 (m, 1H), 2.31 (m, 2H),1.80-1.38 (m, 18H); MS: m/z=342 (M+1) (Calc: 341).

5.3 Example 3

The compound of formula AB (14.40 g, 47.84 mmol) was added to 100 mL ofdry DCE. This mixture was added dropwise to a solution of oxalyldichloride (8.37 g, 66.44 mmol, Sigma-Aldrich) in 200 mL of dry DCE.Under an argon atmosphere, the resulting mixture was magneticallystirred at a temperature of about 25° C. for 1 hr. The mixture was thenwarmed to 60° C. for 10 hrs. The mixture was then cooled to atemperature of about 25° C. and the solvent was removed under reducedpressure. The remaining material was added to 300 mL of MeOH andadsorbed onto silica gel to provide residues that were chromatographedwith a silica gel column eluted with a gradient of from 100%:0%EtOAc:MeOH to 0%:100% EtOAc:MeOH. The product fractions were combinedand concentrated to dryness under reduced pressure to provide 10.0 g ofthe compound of formula BA as a light orange solid (yield 58%).

The identity of the compound of formula BA,1-(1-cyclooctylpiperidin-4-yl)quinoxaline-2,3(1H,4H)-dione, wasconfirmed using ¹H NMR and LC/MS.

Compound BA: ¹H NMR: δ_(H) (400 MHz, CD₃OD): 7.81 (1H, m), 7.31 (3H, m),3.57 (3H, m), 3.43 (2H, m), 3.22 (2H, m), 2.17 (4H, m), 1.99 (4H, m),1.78-1.46 (14H, m); LC/MS (100%, t_(r)=5.011 min): m/z=356.3 [M+H]⁺(Calc: 355.5).

TEA (2 mmol) and POCl₃ (5 mmol, Sigma-Aldrich) were added to asuspension of the compound of formula BA (784 mg, 2 mmol) in toluene (15mL) and DMF (2 mL) at 25° C. The reaction mixture was warmed to 100° C.with stirring. A pale yellow solid formed after 30 min. Thereafter, themixture was cooled to a temperature of about 25° C., filtered, washedtwice with 1:5 EtOAc:Et₂O (10 mL for each wash), and dried under reducedpressure at 60° C. for 12 hr to provide 712 mg ofSubstituted-Quinoxaline-Type Piperidine Compound 404 as a colorlesssolid (yield 87%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 404,3-chloro-1-(1-cyclooctylpiperidin-4-yl)quinoxalin-2(1H)-one, wasconfirmed using ¹H NMR.

Substituted-Quinoxaline-Type Piperidine Compound 404: ¹H NMR: δ_(H) (300MHz, DMSO): 8.11 (1H, br), 7.79 (1H, d, J=8 Hz), 7.67 (1H, m), 7.44 (1H,t, J=8 Hz), 5.11 (1H, br), 3.45-3.30 (4H, m), 3.11 (2H, m), 1.96 (2H,m), 1.73 (2H, d, J=8 Hz), 1.76-1.42 (13H, m).

TEA (0.38 mmol) and 2-aminoethanol (0.57 mmol, Sigma-Aldrich) were addedto a suspension of Substituted-Quinoxaline-Type Piperidine Compound 404(80 mg, 0.19 mmol) in acetonitrile (3 mL) at 25° C. The resultingreaction mixture was stirred at 80° C. for 90 min. After cooling toabout 25° C. and quenching with water (3 mL), a white precipitateformed. The precipitate was filtered, washed with water, and dried underreduced pressure at 60° C. for 12 hr to provide 55 mg ofSubstituted-Quinoxaline-Type Piperidine Compound 3 as light yellow solid(yield 73%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 3,1-(1-cyclooctylpiperidin-4-yl)-3-(2-hydroxyethylamino)quinoxalin-2(1H)-one,was confirmed using ¹H NMR and MS.

Substituted-Quinoxaline-Type Piperidine Compound 3: ¹H NMR: δ_(H) (300MHz, DMSO): 7.66 (1H, m), 7.44-7.32 (2H, m), 7.18 (2H, m), 4.82 (1H, t,J=5.4 Hz), 4.67 (1H, br), 3.58 (2H, q, J=5.7 Hz), 3.47 (2H, q, J=5.7Hz), 2.86-2.68 (5H, m), 2.43-2.36 (2H, m), 1.72-1.41 (16H, m); MS:m/z=436.9 [M+H]⁺ (Calc: 435.4).

5.4 Example 4

In a manner similar to Example 3, the followingSubstituted-Quinoxaline-Type Piperidine Compounds were prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 404.

Substituted-Quinoxaline-Type Piperidine Compound 1 was prepared by usingmorpholine (Sigma-Aldrich) in place of 2-aminoethanol (yield 96%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 1,1-1-yclooctylpiperidin-4-yl)-3-morpholinoquinoxalin-2(1H)-one, wasconfirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 1: ¹H NMR: δ_(H) (400MHz, DMSO): 7.67 (1H, d, J=8 Hz), 7.45 (1H, d, J=8 Hz), 7.28 (2H, t, J=8Hz), 7.21 (2H, t, J=8 Hz), 4.64 (1H, br), 3.77 (4H, m), 3.71 (4H, m),2.84 (2H, m), 2.69-2.61 (3H, m), 2.39 (2H, m), 1.72-1.41 (17H, m);LC/MS: m/z=425.1 [M+H]⁺ (Calc: 424.6).

Substituted-Quinoxaline-Type Piperidine Compound 2 was prepared by usingdimethylamine (Sigma-Aldrich) in place of 2-aminoethanol (yield 92%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 2,1-(1-cyclooctylpiperidin-4-yl)-3-(dimethylamino)quinoxalin-2(1H)-one,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 2: ¹H NMR: δ_(H) (400MHz, DMSO): 7.60 (1H, d, J=8 Hz), 7.40 (1H, d, J=8 Hz), 7.20 (2H, m),4.60 (1H, br), 3.22 (6H, s), 2.84 (2H, m), 2.69-2.62 (3H, m), 2.40 (2H,m), 1.72-1.41 (17H, m); LC/MS: m/z=383.1 [M+H]⁺ (Calc: 382.5).

Substituted-Quinoxaline-Type Piperidine Compound 4 was prepared by usingtert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (ChembasicsPty. Ltd., Perth, Australia) in place of 2-aminoethanol (yield >98%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 4,tert-butyl5-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 4: ¹H NMR: δ_(H) (400MHz, DMSO): 7.61 (1H, d, J=4 Hz), 7.34 (1H, m), 7.22-7.18 (2H, m), 4.65(1H, br), 4.01 (2H, m), 3.71 (1H, m), 3.44 (2H, m), 3.15 (3H, m), 2.92(5H, m), 2.72 (3H, m), 1.78-1.40 (17H, m), 1.39 (9H, s); LC/MS:m/z=550.2 [M+H]⁺ (Calc: 549.8).

Substituted-Quinoxaline-Type Piperidine Compound 6 was prepared by usingphenylmethanamine (Sigma-Aldrich) in place of 2-aminoethanol (yield>98%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 6,3-(benzylamino)-1-(1-cyclooctylpiperidin-4-yl)quinoxalin-2(1H)-one, wasconfirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 6: ¹H NMR: δ_(H) (300MHz, DMSO): 8.08 (1H, m), 7.40-7.19 (9H, m), 4.60 (2H, d, J=6 Hz), 3.41(5H, m), 3.15 (2H, m), 2.10-1.47 (17H, m); LC/MS: m/z=445.1 [M+H]⁺(Calc: 444.6).

Substituted-Quinoxaline-Type Piperidine Compound 7 was prepared by usingtert-butyl 2-aminoethylcarbamate (Sigma-Aldrich) in place of2-aminoethanol (yield 90%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 7,tert-butyl2-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)ethylcarbamate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 7: ¹H NMR: δ_(H) (400MHz, DMSO): 8.00-7.5 (2H, br), 7.43 (1H, m), 7.22 (2H, m), 6.98 (1H, m),4.98 (1H, br), 3.45 (7H, m), 3.21-3.09 (5H, m), 2.04-1.45 (15H, m), 1.37(9H, s); LC/MS: m/z=498.1 [M+H]⁺ (Calc: 497.7).

Substituted-Quinoxaline-Type Piperidine Compound 8 was prepared by usingtert-butyl piperazine-1-carboxylate (Sigma-Aldrich) in place of2-aminoethanol (yield 86%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 8,tert-butyl4-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)piperazine-1-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type. Piperidine Compound 8: ¹H NMR; δ_(H) (400MHz, DMSO): 7.67 (1H, d, J=8 Hz), 7.45 (1H, d, J=8 Hz), 7.29 (1H, d, J=8Hz), 7.21 (1H, d, J=8 Hz), 4.63 (1H, br), 3.75 (4H, s), 3.45 (4H, s),2.84 (2H, m), 2.69-2.61 (3H, m), 2.39 (2H, t, J=8 Hz), 1.71-1.42 (17H,m), 1.42 (9H, s); LC/MS: m/z=524.1 [M+H]⁺ (Calc: 523.7).

Substituted-Quinoxaline-Type Piperidine Compound 18 was prepared byusing piperazin-2-one (Sigma-Aldrich) in place of 2-aminoethanol toprovide a colorless solid (yield 86%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 18,1-(1-cyclooctylpiperidin-4-yl)-3-(3-oxopiperazin-1-yl)quinoxalin-2(1H)-one,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 18: ¹H NMR: δ_(H) (400MHz, CDCl₃): 8.01 (1H, s), 7.83 (1H, m), 7.49 (1H, d, J=7.6 Hz), 7.28(2H, m), 4.94 (1H, br), 4.31 (2H, s), 4.02 (2H, t, J=5.2 Hz), 3.41-3.58(8H, m), 2.01-1.47 (17H, m); LC/MS: m/z=438 [M+H]⁺ (Calc: 437.6).

Substituted-Quinoxaline-Type Piperidine Compound 19 was prepared byusing isoindoline (Sigma-Aldrich) in place of 2-aminoethanol to providea colorless solid (yield 75%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 19,1-(1-cyclooctylpiperidin-4-yl)-3-(isoindolin-2-yl)quinoxalin-2(1H)-one,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 19: ¹H NMR: δ_(H) (300MHz, DMSO): 7.62 (1H, s), 7.41 (3H, s), 7.31 (2H, s), 7.19 (2H, m), 5.23(4H, br), 4.69 (1H, br), 2.87-2.28 (7H, m), 1.78-1.44 (16H, m); LC/MS:m/z=457 [M+H]⁺ (Calc: 456.6).

Substituted-Quinoxaline-Type Piperidine Compound 24 was prepared byusing prop-2-en-1-amine (Sigma-Aldrich) in place of 2-aminoethanol toprovide a colorless solid (yield 90%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 24,3-(allylamino)-1-(1-cyclooctylpiperidin-4-yl)quinoxalin-2(1H)-one, wasconfirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 24: ¹H NMR: δ_(H) (300MHz, DMSO): 7.65 (2H, m), 7.37 (1H, m), 7.18 (2H, m), 5.94 (1H, m), 5.14(2H, m), 4.62 (1H, br), 4.01 (2H, t, J=5.4 Hz), 2.85-2.31 (7H, m),1.73-1.42 (16H, m); LC/MS: m/z=395 [M+H]⁺ (Calc: 394.6).

Substituted-Quinoxaline-Type Piperidine Compound 25 was prepared byusing 3-aminopropane-1,2-diol (Sigma-Aldrich) in place of 2-aminoethanolto provide a colorless solid (yield 77%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 25,1-(1-cyclooctylpiperidin-4-yl)-3-(2,3-dihydroxypropylamino)quinoxalin-2(1H)-one,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 25: ¹H NMR: δ_(H) (300MHz, DMSO): 7.70 (1H, m), 7.38 (1H, m), 7.31 (1H, m), 7.20 (2H, m), 5.02(1H, d, J=5.1 Hz), 4.73 (1H, t, J=5.7 Hz), 4.72 (1H, br), 3.71 (1H, m),3.57 (1H, m), 3.44-3.33 (3H, m), 3.00-2.36 (6H, m), 1.78-1.44 (17H, m);LC/MS: m/z=429 [M+H]⁺ (Calc: 428.6).

Substituted-Quinoxaline-Type Piperidine Compound 119 was prepared byusing pyrazolidin-3-one hydrochloride (Sigma-Aldrich) in place of2-aminoethanol to provide a white amorphous solid (yield 59%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 119,1-(1-cyclooctylpiperidin-4-yl)-3-(3-oxopyrazolidin-1-yl)quinoxalin-2(1H)-one,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 119: ¹H NMR: δ_(H) (300MHz, CDCl₃): 7.64 (1H, br), 7.51 (1H, d, J=4 Hz), 7.25 (2H, m), 4.90(1H, m), 4.44 (2H, d, J=8 Hz), 2.98 (2H, m), 2.80 (2H, d, J=8 Hz), 2.80(1H, m), 2.70 (2H, m), 2.43 (2H, m), 1.75-1.40 (16H, m); LC/MS (100%,t_(r)=1.19 min): m/z=424.2 [M+H]⁺ (Calc: 423.3).

5.5 Example 5

In a manner similar to Example 3, the followingSubstituted-Quinoxaline-Type Piperidine Compound was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 404.

Substituted-Quinoxaline-Type Piperidine Compound 138 was prepared byusing methyl 2-(pyrrolidin-3-yl)acetate in place of 2-aminoethanol(yield 98%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 138,methyl2-(1-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)pyrrolidin-3-yl)acetate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 138: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.53 (1H, br), 7.45 (1H, d, J=8 Hz), 7.13 (2H, m), 4.90(1H, br), 4.12 (1H, br), 4.10 (1H, br), 3.85 (1H, br), 3.71 (3H; s),3.55 (1H, br), 2.95 (2H, d, J=12 Hz), 2.79 (2H, m), 2.65 (2H, m),2.55-2.36 (3H, m), 2.18 (1H, m), 1.90-1.40 (18H, m); LC/MS (99%,t_(r)=1.42 min): m/z=481.2 [M+H]⁺ (Calc: 480.3).

To convert the ester to the acid, to a mixture ofSubstituted-Quinoxaline-Type Piperidine Compound 138 (115 mg, 0.239mmol) and MeOH (4 mL) at a temperature of about 25° C. was added 2Naqueous NaOH (0.14 mL, 0.958 mmol). The resulting reaction mixture waswarmed to a temperature of 50° C. and stirred for 2 h. Afterconcentration under reduced pressure, the reaction mixture was dilutedwith water (5 mL) and extracted with EtOAc (5 mL). The aqueous portionwas neutralized by adding 2N aqueous HCl at a temperature of 0° C.Thereafter, the mixture was extracted twice with EtOAc (10 mL for eachextraction). The organic portions were combined, dried (MgSO₄),filtered, and concentrated under reduced pressure to provide 107 mg ofSubstituted-Quinoxaline-Type Piperidine Compound 111 as a white solid(yield 96%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 111,2-(1-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)pyrrolidin-3-yl)aceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 111: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.61 (1H, m), 7.34 (1H, d, J=8 Hz), 7.14 (2H, m), 4.70 (1H,br), 4.40-3.40 (4H, m), 3.00 (2H, m), 2.80 (4H, m), 2.65 (2H, m), 2.40(2H, m), 2.10 (1H, m), 1.85-1.40 (18H, m); LC/MS (100%, t_(r)=1.32 min):m/z=467.2 [M+H]⁺ (Calc: 466.3).

Methyl 2-(pyrrolidin-3-yl)acetate was prepared as follows:

To a suspension of 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)acetic acid(500 mg, 2.18 mmol, Astatec Pharmaceutical Technology Co.) in DMF (10mL) was added methyl iodide (1634, 2.62 mmol, Sigma-Aldrich) and K₂CO₃(904 mg, 6.53 mmol). These ingredients were stirred at a temperature ofabout 25° C. for 1 h after which the reaction mixture was quenched withwater (20 mL), extracted three times with EtOAc (20 mL for eachextraction), washed twice with water (20 mL for each wash), washed withsaturated aqueous NaCl (10 mL), dried (MgSO₄), and concentrated underreduced pressure to provide tert-butyl3-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate as an oil. To amixture of tert-butyl 3-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate(2.18 mmol) in dioxane (10 mL) at a temperature of about 25° C. wasadded 4N HCl in dioxane (10.8 mmol). Then the reaction mixture wasstirred at 50° C. for 2 h. Thereafter, the mixture was concentratedunder reduced pressure to provide 380 mg of the hydrochloride of methyl2-(pyrrolidin-3-yl)acetate as a colorless oil (yield 96% for two steps),the identity of which was confirmed using ¹H NMR and LC/MS.

Methyl 2-(pyrrolidin-3-yl)acetate: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 9.70(2H, br), 3.70 (3H, s), 3.62 (1H, m), 3.47 (1H, m), 3.30 (1H, m), 3.00(1H, m), 2.74 (1H, m), 2.54 (2H, d, J=8 Hz), 2.26 (1H, m), 1.73 (1H, m);LC/MS (100%, t_(r)=0.34 min): m/z=144.0 [M+H]⁺ (Calc: 143.1).

In a manner similar to Example 3, the followingSubstituted-Quinoxaline-Type Piperidine Compounds were prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 404 then converted fromthe ester to the acid in a manner similar to that described above.

Substituted-Quinoxaline-Type Piperidine Compound 139 was prepared byusing ethyl 3-aminopropanoate (Sigma-Aldrich) in place of 2-aminoethanol(yield >98%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 139,ethyl3-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)propanoate,was confirmed using NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 139: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.60 (1H, br), 7.52 (1H, m), 7.19 (2H, m), 6.69 (1H, m),5.00 (1H, br), 4.17 (2H, q, J=8 Hz), 3.82 (2H, q, J=8 Hz), 2.96 (2H, m),2.80 (2H, m), 2.71 (2H, t, J=8 Hz), 2.50-2.35 (3H, m), 2.01 (2H, m),1.80-1.40 (14H, m); LC/MS (95%, t_(r)=1.47 min): m/z=455.1 [M+H]⁺ (Calc:454.3).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 113,3-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)propanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 113: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.68 (1H, m), 7.47 (1H, m), 7.41 (1H, m), 7.19 (1H, m),5.00-4.30 (2H, m), 3.59 (2H, q, J=8 Hz), 3.50-3.10 (2H, m), 2.91 (2H,m), 2.71 (2H, m), 2.60 (2H, t, J=8 Hz), 2.50 (2H, m), 1.80-1.40 (16H,m); LC/MS (98%, t_(r)=1.34 min): m/z=427.2 [M+H]⁺ (Calc: 426.3).

Substituted-Quinoxaline-Type Piperidine Compound 140 was prepared byusing ethyl 3-aminobutanoate hydrochloride (Sigma-Aldrich) in place of2-aminoethanol (yield 89%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 140,ethyl3-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)butanoate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 140: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.60 (1H, br), 7.52 (1H, m), 7.19 (2H, m), 6.57 (1H, d, J=8Hz), 5.00 (1H, br), 4.60 (1H, m), 4.14 (2H, q, J=8 Hz), 3.20-2.30 (9H,m), 2.00-1.40 (16H, m), 1.37 (3H, d, J=8 Hz), 1.26 (3H, t, J=8 Hz);LC/MS (100%, t_(r)=1.52 min): m/z=469.2 [M+H]⁺ (Calc: 468.3).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 116,3-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)butanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 116: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.60 (1H, m), 7.40 (1H, m), 7.06 (2H, m), 5.70-5.00 (2H,m), 4.55 (1H, m), 3.40-3.20 (3H, m), 3.02 (2H, m), 2.80-2.60 (4H, m),1.96 (2H, m), 1.80-1.38 (14H, m), 1.41 (3H, d, J=8 Hz); LC/MS (100%,t_(r)=1.47 min): m/z=441.2 [M+H]⁺ (Calc: 440.3).

Substituted-Quinoxaline-Type Piperidine Compound 141 was prepared byusing ethyl 2-aminopropanoate hydrochloride (Sigma-Aldrich) in place of2-aminoethanol (yield 92%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 141,ethyl2-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)propanoate,was confirmed using NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 141: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.60 (1H, br), 7.50 (1H, m), 7.19 (2H, m), 6.73 (1H, d, J=8Hz), 4.75 (1H, m), 4.23 (2H, q, J=8 Hz), 2.97 (2H, m), 2.80 (2H, m),2.67 (1H, m), 2.43 (2H, m), 1.85-1.40 (16H, m), 1.56 (3H, d, J=4 Hz),1.29 (3H, t, J=8 Hz); LC/MS (100%, t_(r)=1.55 min): m/z=455.2 [M+H]⁺(Calc: 454.3).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 118,2-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)propanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 118: ¹H NMR: δ_(H) (400MHz, DMSO): 7.77 (1H, m), 7.50 (1H, d, J=8 Hz), 7.39 (1H, m), 7.19 (2H,m), 4.80 (1H, br), 4.39 (1H, m), 3.20-2.85 (7H, m), 2.00-1.40 (16H, m),1.44 (3H, d, J=8 Hz); LC/MS (100%, t_(r)=1.54 min): m/z=427.2 [M+H]⁺(Calc: 426.3).

Substituted-Quinoxaline-Type Piperidine Compound 142 was prepared byusing methyl pyrrolidine-3-carboxylate hydrochloride (Sigma-Aldrich) inplace of 2-aminoethanol (yield 71%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 142,methyl1-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)pyrrolidine-3-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 142: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.55 (1H, br), 7.50 (1H, d, J=8 Hz), 7.14 (2H, m), 4.90(1H, br), 4.30-3.90 (4H, m), 3.72 (3H, s), 3.13 (1H, m), 2.95 (2H, m),2.79 (2H, m), 2.67 (1H, m), 2.42 (2H, m), 2.23 (2H, m), 1.90-1.40 (18H,m); LC/MS (98%, t_(r)=1.46 min): m/z=467.1 [M+H]⁺ (Calc: 466.3).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 109,1-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)pyrrolidine-3-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 109: ¹H NMR: δ_(H) (400MHz, DMSO): 7.76 (1H, br), 7.36 (1H, m), 7.16 (2H, m), 4.90 (1H, br),4.20-3.70 (4H, m), 3.60-2.90 (8H, m), 2.20-1.90 (4H, m), 1.80-1.40 (14H,m); LC/MS (100%, t_(r)=1.38 min): m/z=453.3 [M+H]⁺ (Calc: 452.3).

A mixture of the compound of formula CA (3-nitropyridin-2-amine, 1.39 g,10 mmol, Sigma-Aldrich), (BOC)₂O (20 mmol), and DMAP (catalytic amount,Sigma-Aldrich) in THF (28 mL) was stirred at 90° C. for lhr. Aftercooling to a temperature of about 25° C. and quenching with water (10mL) the mixture was extracted three times with EtOAc, dried (MgSO₄), andconcentrated under reduced pressure. At a temperature of about 25° C.,the resulting yellow oil was mixed with MeOH (33 mL) then added to K₂CO₃(30 mmol). The reaction mixture was stirred at 60° C. for 1 hr. Aftercooling to a temperature of about 25° C., 2N aqueous HCl (10 mL) wasadded and the pH was adjusted to be within the range of from about 7 toabout 8. Thereafter, the mixture was extracted three times with EtOAc,dried (MgSO₄), and concentrated under reduced pressure. The resultingoil was chromatographed with a silica gel column eluted with a gradientof from 10%:90% EtOAc:n-hexane to 50%:50% EtOAc:n-hexane to provide thecompound of formula CB as a yellow solid (yield 91%).

The identity of the compound of formula CB, tert-butyl3-nitropyridin-2-ylcarbamate, was confirmed using ¹H NMR.

Compound CB: ¹H NMR: δ_(H) (300 MHz, CDCl₃): 9.59 (1H, s), 8.72 (1H, dd,J=4.5, 1.5 Hz), 8.5 (1H, dd, J=8.4, 1.5 Hz), 7.14 (1H, dd, J=8.4, 4.8Hz), 1.56 (9H, s).

Under a hydrogen atmosphere, a mixture of the compound of formula CB(2.11 g, 9.07 mmol), 10% palladium on carbon (210 mg, Sigma-Aldrich),and MeOH (35 mL) was stirred at a temperature of about 25° C. for 16 hr.After the Pd/C was filtered off, the mixture was washed with EtOAc andMeOH, and the filtrate was concentrated under reduced pressure. Theresulting solid was suspended with 3:2 n-hexane:diethyl ether which wasfiltered and washed with n-hexane to provide the compound of formula CCas a pale yellow solid (yield 87%).

The identity of the compound of formula CC, tert-butyl3-aminopyridin-2-ylcarbamate, was confirmed using ¹H NMR.

Compound CC: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.76 (1H, d, J=1.5 Hz),7.10 (1H, dd, J=8.4, 1.5 Hz), 6.99 (1H, dd, J=8.4, 4.8 Hz), 1.52 (9H,s).

A mixture of the compound of formula CC (710 mg, 3.4 mmol), the compoundof formula AA (5.1 mmol), NaBH(OAc)₃ (10.2 mmol) and AcOH (5.1 mmol) inCHCl₃ (18 mL) was stirred at a temperature of about 25° C. for 16 hr.After quenching with saturated NaHCO₃ solution, the mixture wasextracted with CHCl₃, dried (MgSO₄), and concentrated under reducedpressure. The residue was chromatographed with an amino-silica gelcolumn (Yamazen Corp. W091-01) eluted with a gradient of from 5%:95%EtOAc:n-hexane to 20%:80% EtOAc:n-hexane to 50%:50% EtOAc:n-hexane toprovide the compound of formula CD as a colorless solid (yield 63%).

The identity of the compound of formula CD, tert-butyl3-(1-cyclooctylpiperidin-4-ylamino)pyridin-2-ylcarbamate, was confirmedusing ¹H NMR.

Compound CD: ¹H NMR: δ_(H) (400 MHz, DMSO-d₆): 8.59 (1H, s), 7.60 (1H,t, J=4 Hz), 7.01 (2H, d), 4.67 (1H, d, J=8 Hz), 3.25 (1H, m), 2.67 (2H,m), 2.35-2.30 (2H, m), 1.88-1.85 (2H, m), 1.69-1.60 (2H, m), 1.56-1.32(25H, m).

To a suspension of the compound of formula CD (317 mg, 0.79 mmol) inEtOAc (5 mL) at a temperature of about 25° C. was added 4N HCl in EtOAc(7.9 mmol) which was stirred at about 25° C. for lhr and then for 3 hrmore at 50° C. After neutralization with 28% aqueous ammonia, the pH wasadjusted to be within the range of from about 13 to about 14.Thereafter, the mixture was extracted three times with EtOAc, theorganic portions were combined, dried (MgSO₄), and concentrated underreduced pressure to provide 237 mg of the compound of formula CE as abrown solid (yield >98%).

The identity of the compound of formula CE,N³-(1-cyclooctylpiperidin-4-yl)pyridine-2,3-diamine, was confirmed using¹H NMR.

Compound CE: ¹H NMR: δ_(H)(400 MHz, CDCl₃): 7.80 (1H, d, J=4 Hz), 7.66(1H, s), 6.39 (1H, d, J=4 Hz), 4.12 (1H, m), 2.79 (1H, m), 2.68-2.61(6H, m), 2.43 (2H, m), 1.92-1.48 (24H, m).

To a mixture of the compound of formula CE (168 mg, 0.79 mmol) in CH₂Cl₂(10 mL) at 0° C. was added dropwise over 10 min methyl2-chloro-2-oxoacetate (0.79 mmol, Sigma-Aldrich) in CH₂Cl₂ (3 mL). Theresulting reaction mixture was stirred at 0° C. for 30 min. Afterquenching with saturated NaHCO₃ solution, the mixture was extractedthree times with CHCl₃. Thereafter, the organic portions were combined,dried (MgSO₄), and concentrated under reduced pressure. At a temperatureof about 25° C., the resulting oil was mixed with ethanol (4 mL) and themixture was then added to sodium methoxide (1.09 mmol, Sigma-Aldrich).The reaction mixture was stirred at 70° C. for 1 hr. After concentrationunder reduced pressure, to the resulting oil was added water (0.5 mL)and 2N HCl (1 mL). The resulting precipitate was filtered, washed with90%:10% water:MeOH, and dried under reduced pressure at 60° C. for 12 hrto provide the dihydrochloride of the compound of formula CF as acolorless solid.

The identity of the compound of formula CF,1-(1-cyclooctylpiperidin-4-yl)pyrido[3,2-b]pyrazine-2,3(1H,4H)-dione,was confirmed using ¹H NMR and LC/MS.

Compound CF: ¹H NMR: δ_(H) (300 MHz, DMSO-d₆): 12.39 (1H, s), 9.8 (1H,br), 8.27 (1H, m), 8.14 (1H, d, J=4.5 Hz), 7.21 (1H, dd, J=4.5, 8.1 Hz),4.91 (1H, m), 3.45-3.3 (6H, m), 2.99 (2H, m), 2.02 (2H, m), 1.99 (2H,m), 1.58-1.46 (11H, m); LC/MS: m/z=357 [M+H]⁺ (Calc: 356.5).

Phosphoryl chloride (1.85 mmol, Sigma-Aldrich) was added to a suspensionof the compound of formula CF (220 mg, 0.62 mmol) and DMA (1.85 mmol,Sigma-Aldrich) in toluene (6 mL) and DMF (1 mL) at 25° C. The resultingreaction mixture was stirred at 100° C. for 45 min. After cooling to atemperature of about 25° C. and quenching with water, the mixture wasextracted three times with CHCl₃/water, dried (Na₂SO₄), and concentratedunder reduced pressure to provide 187 mg of the compound of formula CGas a brown solid (yield 81%).

The identity of the compound of formula CG,3-chloro-1-(1-cyclooctylpiperidin-4-yl)pyrido[3,2-b]pyrazin-2(1H)-one,was confirmed using LC/MS.

Compound CG: LC/MS: m/z=375 [M+H]⁺ (Calc: 374.2).

TEA (0.21 mmol) and tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.21 mmol) were addedto a suspension of the compound of formula CG (80 mg, 0.21 mmol) inacetonitrile (3 mL) at 25° C. The resulting reaction mixture was stirredat 80° C. for 2 hr. After cooling to a temperature of about 25° C. andquenching with water (3 mL), the mixture was extracted three times withCHCl₃/water, dried (Na₂SO₄), and concentrated under reduced pressure toprovide a yellow oil. The oil was chromatographed with a silica gelcolumn eluted with a gradient of from 97%:3% CHCl₃:MeOH to 90%:10%CHCl₃:MeOH to provide 68 mg of Substituted-Quinoxaline-Type PiperidineCompound 97 as a yellow amorphous solid (yield 62%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 97,tert-butyl5-(1-(1-cyclooctylpiperidin-4-yl)-2-oxo-1,2-dihydropyrido[3,2-b]pyrazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate,was confirmed using ¹H NMR.

Substituted-Quinoxaline-Type Piperidine Compound 97: ¹H NMR: δ_(H) (400MHz, CDCl₃): 8.33 (1H, d, J=4.8 Hz), 7.87 (1H, m), 7.04 (1H, m), 4.46(1H, m), 4.20 (1H, m), 4.00 (1H, m), 3.82 (1H, m), 3.62 (2H, m), 3.30(2H, m), 2.96 (4H, m), 2.66 (2H, m), 2.41 (2H, m), 1.75-1.44 (26H, m).

To a suspension of Substituted-Quinoxaline-Type Piperidine Compound 4(120 mg, 0.22 mmol) in 1,4-dioxane (4 mL) and MeOH (1 mL) was added 4NHCl in 1,4-dioxane (2 mL) at a temperature of about 25° C. The reactionmixture was stirred at 25° C. for 1 hr. The resulting precipitate wasfiltered, washed with diethyl ether (3 mL), and dried under reducedpressure at 70° C. to provide 123 mg of Substituted-Quinoxaline-TypePiperidine Compound 5 as a colorless solid (yield >98%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 5,1-(1-cyclooctylpiperidin-4-yl)-3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinoxalin-2(1H)-one,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 5: ¹H NMR: δ_(H) (400MHz, DMSO): 9.67-9.54 (3H, br), 7.91 (1H, br), 7.53 (1H, s), 7.22 (2H,m), 5.03 (1H, br), 4.50-3.90 (12H, m), 3.41-3.00 (6H, m), 2.07 (2H, m),1.89-1.43 (13H, m); LC/MS: m/z=450.1 [M+H]⁺ (Calc: 449.6).

To a mixture of Substituted-Quinoxaline-Type Piperidine Compound 5 (180mg, 0.328 mmol) and CH₂Cl₂ (4 mL) at 0° C. was added pyridine (934,1.148 mmol) and ethyl 2-chloro-2-oxoacetate (92 μL, 0.820 mmol,Sigma-Aldrich). After heating to a temperature of about 25° C. thereaction mixture was stirred for 2 h. The reaction mixture was dilutedwith water (5 mL) then extracted three times with CHCl₃ (10 mL for eachextraction). The organic portions were combined, washed with saturatedaqueous NaCl (10 mL), dried (MgSO₄), filtrated, and concentrated underreduced pressure. The residue was chromatographed with an amino-silicagel column (Yamazen Corp. W091-01) eluted with a gradient of from10%:90% EtOAc:n-hexane to 50%:50% EtOAc:n-hexane to provide 89 mg ofSubstituted-Quinoxaline-Type Piperidine Compound 173 as a whiteamorphous solid (yield 47%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 173,ethyl2-(5-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-oxoacetate,was confirmed using ¹H NMR and MS.

Substituted-Quinoxaline-Type Piperidine Compound 173: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.46 (1H, m), 7.32 (1H, m), 7.18 (2H, m), 5.20 (1H, br),4.31 (2H, q, J=8.0 Hz), 4.20 (2H, m), 3.95-3.85 (4H, m), 3.70-3.50 (4H,m), 3.00 (2H, m), 2.40-1.90 (5H, m), 1.90-1.45 (18H, m), 1.39 (3H, t,J=8.0 Hz); MS: m/z=576 [M+H]⁺ (Calc: 575.3).

To a mixture of Substituted-Quinoxaline-Type Piperidine Compound 173 (85mg, 0.148 mmol) in MeOH (4 mL) at a temperature of about 25° C. wasadded 2N aqueous NaOH (0.15 mL, 0.295 mmol). The reaction mixture wasstirred for 2 h at a temperature of about 25° C. After concentrationunder reduced pressure, the mixture was diluted with water (5 mL) thenextracted with EtOAc (5 mL). The aqueous portion was neutralized byadding a first treatment of 2N aqueous HCl at a temperature of 0° C.Thereafter, the mixture was extracted twice with CHCl₃ (10 mL for eachextraction). The organic portions were combined, dried (MgSO₄),filtrated, and concentrated under reduced pressure to provide a whitesolid. To the solid was added water (2 mL) then a second treatment of 2Naqueous HCl (1 mL). Thereafter, the mixture was concentrated underreduced pressure to provide 77 mg of the hydrochloride ofSubstituted-Quinoxaline-Type Piperidine Compound 174 (yield 89%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound174,2454441-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-oxoaceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 174: ¹H NMR: δ_(H) (400MHz, DMSO): 10.62 (0.9H, m), 9.84 (0.1H, m), 7.83 (0.9H, m), 7.72 (0.1H,m), 7.60 (1H, m), 7.28 (2H, m), 5.86 (1H, m), 4.40-4.00 (6H, m),3.90-3.35 (4H, m), 3.10 (2H, m), 2.97 (1H, m), 2.60 (2H, m), 2.40-1.30(20H, m); LC/MS (100%, t_(r)=1.45 min): m/z=548 [M+H]⁺ (Calc: 547.3).

5.8 Example 8

In a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 5 in Example 7, the followingSubstituted-Quinoxaline-Type Piperidine Compounds were prepared.

The trihydrochloride of Substituted-Quinoxaline-Type Piperidine Compound9 was prepared by using Substituted-Quinoxaline-Type Piperidine Compound7 in place of Substituted-Quinoxaline-Type Piperidine Compound 4 (yield90%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 9,3-(2-aminoethylamino)-1-(1-cyclooctylpiperidin-4-yl)quinoxalin-2(1H)-one,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 9: ¹H NMR: δ_(H) (400MHz, DMSO): 8.10-7.80 (4H, br), 7.50 (1H, s), 7.25 (2H, m), 5.00 (1H,br), 3.68 (2H, d, J=4 Hz), 3.43-3.39 (5H, m), 3.19-3.08 (4H, m), 2.06(2H, s), 1.99-1.19 (15H, m); LC/MS: m/z=398.1 [M+H]⁺ (Calc: 397.6).

The trihydrochloride of Substituted-Quinoxaline-Type Piperidine Compound10 was prepared by using Substituted-Quinoxaline-Type PiperidineCompound 8 in place of Substituted-Quinoxaline-Type Piperidine Compound4 (yield 98%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 10,1-(1-cyclooctylpiperidin-4-yl)-3-(piperazin-1-yl)quinoxalin-2(1H)-one,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 10: ¹H NMR: δ_(H) (400MHz, DMSO): 9.53 (1H, s), 7.53 (1H, d, J=4 Hz), 7.33-7.26 (2H, m), 5.39(1H, br), 4.04 (4H, s), 3.42-3.35 (5H, m), 3.20 (4H, s), 1.99 (2H, s),1.73-1.43 (15H, m); LC/MS: m/z=424.1 [M+H]⁺ (Calc: 423.6).

Substituted-Quinoxaline-Type Piperidine Compound 87 was prepared byusing Substituted-Quinoxaline-Type Piperidine Compound 97 in place ofSubstituted-Quinoxaline-Type Piperidine Compound 4 (yield 82%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 87,1-(1-cyclooctylpiperidin-4-yl)-3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrido[3,2-b]pyrazin-2(1H)-one,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 87: ¹H NMR: δ_(H) (400MHz, DMSO): 10.0 (1H, m), 9.58 (1H, m), 8.89 (1H, br), 8.26 (1H, d,J=5.2 Hz), 7.44 (1H, m), 5.15 (1H, br), 4.42-4.36 (3H, m), 3.95-3.88(3H, m), 3.56-3.02 (11H, m), 2.08-1.44 (16H, m); LC/MS: m/z=451 [M+H]⁺(Calc: 450.6).

In a manner similar to Example 3, the hydrochloride ofSubstituted-Quinoxaline-Type Piperidine Compound 161, (S)-tert-butyl1-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)pyrrolidin-3-ylcarbamate,was prepared from Substituted-Quinoxaline-Type Piperidine Compound 404by using (S)-tert-butyl pyrrolidin-3-ylcarbamate (Sigma-Aldrich) inplace of 2-aminoethanol. Thereafter, in a manner similar to thepreparation of Substituted-Quinoxaline-Type Piperidine Compound 5 inExample 7, Substituted-Quinoxaline-Type Piperidine Compound 162 wasprepared from Substituted-Quinoxaline-Type Piperidine Compound 161(yield 98% for two steps).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 162,(S)-3-(3-aminopyrrolidin-1-yl)-1-(1-cyclooctylpiperidin-4-yl)quinoxalin-2(1H)-one,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 162: ¹H NMR: δ_(H) (400MHz, CD₃OD): 7.64 (1H, br), 7.41 (1H, br), 7.14 (2H, m), 4.08 (2H, m),3.93 (1H, m), 3.72 (1H, m), 3.57 (1H, m), 3.02 (2H, d, J=12 Hz), 2.91(2H, m), 2.77 (1H, m), 2.54 (2H, m), 2.14 (1H, m), 1.90-1.45 (18H, m);LC/MS (99%, t_(r)=0.58 min): m/z=424.3 [M+H]⁺ (Calc: 423.3).

TEA (0.316 mmol) and methansulfonyl chloride (0.087 mmol, Sigma-Aldrich)were added to a mixture of Substituted-Quinoxaline-Type PiperidineCompound 9 (40 mg, 0.079 mmol) in CH₂Cl₂ at 0° C. and the resultingreaction mixture was stirred for 3 hr. Thereafter, an additional portionof methansulfonyl chloride (0.174 mmol) was added and the reactionmixture was stirred at 50° C. for 7 hr. After cooling to a temperatureof about 25° C., the mixture was extracted three times with CHCl₃/water,dried (MgSO₄), and concentrated under reduced pressure to provide acolorless oil. The oil was chromatographed with a silica gel columneluted with a gradient of from 95%:5% CHCl₃:MeOH to 90%:10% CHCl₃:MeOHto provide 27 mg of Substituted-Quinoxaline-Type Piperidine Compound 11as a colorless solid (yield 73%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 11,N-(2-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)ethyl)methanesulfonamide,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 11: ¹H NMR: δ_(H)(400MHz, DMSO): 7.68 (1H, m), 7.57 (1H, m), 7.25-7.15 (2H, m), 3.53 (2H, t),3.23 (2H, m), 2.93 (3H, s), 2.85-2.55 (4H, m), 2.45-2.30 (5H, m),1.80-1.40 (14H, m); LC/MS (100%): m/z=476.7 [M+H]⁺ (Calc: 476.1).

5.10 Example 10

Substituted-Quinoxaline-Type Piperidine Compound 5 (100 mg, 0.18 mmmol),39% formaldehyde (0.27 mmol, Sigma-Aldrich), NaBH(OAc)₃ (0.54 mmol), andsodium acetate (0.54 mmol, Sigma-Aldrich) were added to CHCl₃ (5 mL) andthe resulting reaction mixture was stirred at 25° C. for 16 hr. Afterquenching with saturated NaHCO₃ solution, the mixture was extracted withCHCl₃/water. Thereafter, the organic portion was dried (MgSO₄) andconcentrated under reduced pressure. The residue was chromatographedwith an amino-silica gel column (Yamazen Corp. W091-01) eluted with agradient of from 30%:70% EtOAc:n-hexane to 70%:30% EtOAc:n-hexane toprovide Substituted-Quinoxaline-Type Piperidine Compound 12 as acolorless solid (yield 75%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 12,1-(1-cyclooctylpiperidin-4-yl)-3-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinoxalin-2(1H)-one,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 12: ¹H NMR: δ_(H) (400MHz, DMSO): 7.61 (1H, d, J=8 Hz), 7.36 (1H, t, J=4 Hz), 7.19-7.13 (2H,m), 4.66 (1H, br), 3.96 (3H, s), 3.78 (3H, m), 2.95-2.54 (10H, m), 2.22(3H, s), 1.74-1.43 (17H, m); LC/MS: m/z=464.1 [M+H]⁺ (Calc: 463.7).

5.11 Example 11

TEA (0.9 mmol) and acetyl chloride (0.27 mmol, Sigma-Aldrich) were addedto a mixture of Substituted-Quinoxaline-Type Piperidine Compound 5 (100mg, 0.18 mmol) in CH₂Cl₂ at 0° C. The resulting reaction mixture wasstirred at 0° C. for 1 hr. After heating to a temperature of about 25°C., the mixture was extracted three times with CHCl₃/water, dried(MgSO₄), and concentrated under reduced pressure to provide a colorlessoil. The oil was chromatographed with a silica gel column eluted with agradient of from 97%:3% CHCl₃:MeOH to 90%:10% CHCl₃:MeOH to 85%:15%CHCl₃:MeOH to provide 64 mg of Substituted-Quinoxaline-Type PiperidineCompound 13 as a colorless solid (yield 73%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 13,3-(5-acetylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(1-cyclooctylpiperidin-4-yl)quinoxalin-2(1H)-one, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 13: ¹H NMR: δ_(H) (400MHz, DMSO): 7.58 (1H, d, J=8 Hz), 7.35 (1H, t, J=4 Hz), 7.18-7.13 (2H,m), 4.61 (1H, br), 4.03 (1H, br), 3.68 (2H, dd, J=4 Hz), 3.54 (1H, dd,J=4 Hz), 3.40 (1H, m), 3.24 (1H, m), 2.99-2.40 (7H, m), 2.38 (2H, t,J=12 Hz), 1.93-1.43 (17H, m); LC/MS: m/z=492.1 [M+H]⁺ (Calc: 491.7).

5.12 Example 12

Diethyl 2-oxomalonate (5 mmol, Sigma-Aldrich) was added dropwise to asuspension of the compound of formula AB (1507 mg, 5 mmol) in toluene(15 mL) at 25° C. The resulting reaction mixture was stirred at 130° C.for 4 hr. After cooling to a temperature of about 25° C. andconcentrating under reduced pressure, a red oil was obtained. The oilwas chromatographed with a silica gel column eluted with a gradient offrom 99%:1% CHCl₃:MeOH to 95%:5% CHCl₃:MeOH to provide a red amorphoussolid. The solid was chromatographed with a silica gel column elutedwith a gradient of from 95%:5% EtOAc:MeOH to 90%:10% EtOAc:MeOH toprovide 1100 mg of Substituted-Quinoxaline-Type Piperidine Compound 70as a colorless solid (yield 53%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 70,ethyl4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 70: ¹H NMR: δ_(H) (300MHz, DMSO): 7.95 (1H, d, J=8.7 Hz), 7.87 (1H, dd, J=7.8, 1.8 Hz), 7.31(1H, t, J=7.2 Hz), 7.44 (1H, t, J=6.9 Hz), 4.78 (1H, br), 4.37 (2H, d,J=7.2 Hz), 2.85 (2H, m), 2.60-2.34 (5H, m), 1.70-1.42 (16H, m), 1.32(3H, t, J=7.2 Hz); LC/MS: m/z=412 [M+H]⁺ (Calc: 411.5).

2N NaOH (0.25 mmol) was added to a mixture ofSubstituted-Quinoxaline-Type Piperidine Compound 70 (104 mg, 0.25 mmol)in ethanol at 25° C. The resulting reaction mixture was stirred at 50°C. for 90 min. After concentration under reduced pressure, the resultingyellow solid was dried under reduced pressure at 80° C. for 12 hr toprovide 100 mg of the sodium salt of Substituted-Quinoxaline-TypePiperidine Compound 71 as a yellow solid (yield >98%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 71,4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 71: ¹H NMR: δ_(H) (300MHz, DMSO): 7.76 (1H, d, J=8.4 Hz), 7.64 (1H, dd, J=7.8, 1.5 Hz), 7.48(1H, t, J=8.4 Hz), 7.28 (1H, t, J=7.5 Hz), 4.67 (1H, br), 2.87-2.34 (7H,m), 1.71-1.42 (16H, m); LC/MS: m/z=384 [M+H]⁺ (Calc: 383.5).

Diphenylphosphoryl azide (“DPPA”, 1.2 mmol, Sigma-Aldrich) was added toa mixture of the sodium salt of Substituted-Quinoxaline-Type PiperidineCompound 71 (120 mg, 0.3 mmol) in tert-BuOH (i.e., 2-methylpropan-2-ol)at 25° C. Thereafter, the reaction mixture was warmed to a temperatureof 100° C. and stirred for 3.5 h. After cooling to about 25° C. andquenching with saturated NaHCO₃ solution, the mixture was extractedthree times with EtOAc/water, dried (MgSO₄), and concentrated underreduced pressure to provide an orange oil. The oil was chromatographedwith a silica gel column eluted with a gradient of from 99%:1%CHCl₃:MeOH to 95%:5% CHCl₃:MeOH to provide 124 mg ofSubstituted-Quinoxaline-Type Piperidine Compound 14 as a pale yellowamorphous solid (yield 91%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 14,tert-butyl4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylcarbamate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 14: ¹H NMR: δ_(H) (300MHz, DMSO): 8.84 (1H, s), 7.83 (1H, d, J=8.7 Hz), 7.60 (1H, d, J=7.8Hz), 7.47 (1H, t, J=7.9 Hz), 7.34 (1H, t, J=7.2 Hz), 4.69 (1H, br),2.83-2.42 (8H, m), 1.71-1.43 (24H, m); LC/MS: m/z=455.1 [M+H]⁺ (Calc:454.6).

Substituted-Quinoxaline-Type Piperidine Compound 15 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 14 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound 5in Example 7 (yield 84%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 15,3-amino-1-(1-cyclooctylpiperidin-4-yl)quinoxalin-2(1H)-one, wasconfirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 15: ¹H NMR: δ_(H) (400MHz, DMSO): 7.65 (1H, d, J=8 Hz), 7.33 (1H, m), 7.19 (2H, m), 7.01 (2H,br), 4.72 (1H, br), 4.04 (4H, s), 2.85 (2H, d, J=12 Hz), 2.69-2.50 (3H,m), 2.40 (2H, m), 1.71-1.43 (16H, m); LC/MS: m/z=355.1 [M+H]⁺ (Calc:354.5).

Substituted-Quinoxaline-Type Piperidine Compound 17 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 15 in a manner similarto Example 11 (yield 78%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 17,N-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)acetamide,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 17: ¹H NMR: δ_(H) (300MHz, DMSO): 9.65 (1H, s), 7.90 (1H, br), 7.63 (1H, d, J=6.3 Hz), 7.49(1H, t, J=8.4 Hz), 7.35 (1H, t, J=7.5 Hz), 4.78 (1H, Br), 3.25-2.52 (6H,m), 2.37 (3H, s), 1.90-1.42 (17H, m); LC/MS: m/z=397 [M+H]⁺ (Calc:396.5).

At a temperature of 0° C., trifluoromethanesulfonic anhydride (41.44,0.246 mmol, Sigma-Aldrich) and TEA (86.24, 0.615 mmol) were added to amixture of Substituted-Quinoxaline-Type Piperidine Compound 15 (80 mg,0.205 mmol) in CH₂Cl₂ (3 mL). After warming it to a temperature of about25° C., the reaction mixture was stirred for 5.5 h. After cooling to 0°C., the mixture was quenched with saturated aqueous NaHCO₃ (5 mL) andextracted three times with CHCl₃ (5 mL for each extraction). The organicportions were combined, dried (MgSO₄), filtered, and concentrated underreduced pressure to provide a residue. The residue was triturated withMeOH, filtered, rinsed with MeOH, and collected to provide 36 mg ofSubstituted-Quinoxaline-Type Piperidine Compound 117 as a white solid(yield 36%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 117:N-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)-1,1,1-trifluoromethanesulfonamide,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 117: ¹H NMR: δ_(H) (400MHz, DMSO): 9.10 (1H, br), 7.68 (1H, d, J=8 Hz), 7.35 (1H, d, J=8 Hz),7.24 (1H, t, J=8 Hz), 7.17 (1H, t, J=8 Hz), 4.90 (1H, m), 3.50-3.30 (3H,m), 3.10 (2H, m), 2.00-1.40 (18H, m); LC/MS: (100%, t_(r)=1.91 min):[M+H]⁺ (Calc: 486.2).

5.13 Example 13

A mixture of the compound of formula DA (tropinone, 200 g, 1.438 mol,Sigma-Aldrich) and acetone (1 L) was cooled to 0° C. Dimethyl sulfate(143 mL, 1.5098 mol, Sigma-Aldrich) was added dropwise over 30 min andthe resulting reaction mixture was stirred for 3 h, then filtered. Thefilter cake was dried under reduced pressure for 18 h to provide 380 gof a compound of formula DB as a white solid (yield >98%).

The identity of the compound of formula DB, tropinone dimethylsulfatesalt, was confirmed using ¹H NMR.

Compound DB: ¹H NMR: δ_(H) (400 MHz, DMSO-d₆): 4.14 (2H, m), 3.40 (3H,s), 3.38 (3H, s), 3.32 (1H, m), 3.12 (1H, m), 2.55-2.40 (4H, m), 1.96(2H, m).

A mixture of the compound of formula DB (40 g, 150.8 mmol) and water (70mL) was added dropwise to a boiling mixture of 1-adamantylamine (22.8 g,150.8 mmol, Sigma-Aldrich) in ethanol (250 mL) containing K₂CO₃ (2.1 g,15 mmol). The reaction mixture was refluxed an additional 3 h thenevaporated to dryness under reduced pressure to provide a residue. Theresidue was partitioned between EtOAc (500 mL) and 1M K₂CO₃ solution(500 mL). The organic phase was separated and the aqueous phase wasextracted with EtOAc (500 mL). The organic portions were combined, dried(MgSO₄), and evaporated to dryness under reduced pressure to provide abrown oil. Flash chromatography of the oil with a silica gel columneluting with 3:10 hexanes:EtOAc provided 5.0 g of a compound of formulaDC as a pale yellow solid (yield 13%).

The identity of the compound of formula DC,8-adamantan-1-yl-8-aza-bicyclo[3.2.1]octan-3-one, was confirmed using ¹HNMR.

Compound DC: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 3.96 (2H, m), 2.50 (2H, dd,J=16.0, 4.5 Hz), 2.27 (2H, dd, J=16, 1.7 Hz), 2.07 (2H, m), 1.78 (2H,m), 1.71-1.56 (15H, m).

Sodium tetrahydroborate (9.46 g, 250 mmol, Sigma-Aldrich) was suspendedin dry CH₂Cl₂ (500 mL). 2-Ethylhexanoic acid (126.2 g, 875 mmol,Sigma-Aldrich) was added and the mixture stirred at a temperature ofabout 25° C. for 16 h. The resulting borohydrate reagent, believed tocomprise sodium tris(2-ethylhexanoyloxy)hydroborate and assumed to havea molarity of 0.5M, was held for later use.

To a mixture of the compound of formula DC (5.2 g, 20.05 mmol),1,2-phenylenediamine (4.34 g, 40.1 mmol), and CH₂Cl₂ (50 mL) was added2-ethylhexanoic acid (5.2 mL, 20.05 mmol). Under a nitrogen atmosphere,the resulting mixture was cooled to 0° C. with stirring. The borohydridereagent (0.5M, 120.3 mL, 60.15 mmol), previously prepared as describedabove, was added and the reaction mixture was stirred for 18 h. Themixture was partitioned between EtOAc (400 mL) and 2M sodium carbonate(400 mL). The organic phase was separated, dried (MgSO₄), and evaporatedto dryness under reduced pressure to provide a residue. Flashchromatography of the residue with a silica gel column eluting with 1:1EtOAc:hexanes followed by eluting with 100:100:10:1EtOAc:hexanes:MeOH:ammonia provided 5 g of the compounds of formula DDand DE as an approximately 2:1 mixture of endo:exo (DD:DE isomers (yield71%).

The identity of the compound of formula DD:DE isomeric mixture,N-(8-adamantan-1-yl-8-aza-bicyclo[3.2.1]oct-3-yl)-benzene-1,2-diamine,was confirmed using ¹H NMR.

Compounds DD:DE: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 6.82-6.50 (4H[isomer1+2], m), 3.90-3.60 (3H[isomer 1+2], m), 2.55-1.96 (11H[isomer 1+2], m),1.87-1.52 (15H[isomer 1+2], m).

The above DD:DE mixture (5.0 g, 14.22 mmol) and diethyl 2-oxomalonate(3.25 mL, 21.3 mmol, Sigma-Aldrich) were dissolved in dry toluene (100mL). Powdered 4 Å molecular sieves (5 g) were added and the reactionmixture was refluxed for 7 h. The mixture was cooled then evaporated todryness under reduced pressure to provide a residue. Flashchromatography of the residue with a silica gel column eluting with 3:1hexanes:EtOAc provided two fractions—less polar fraction 1 and morepolar fraction 2. Less polar fraction 1 was triturated with diethylether (25 mL) to provide 930 mg of a yellow solid. LC/MS showed thismaterial to be a mixture of Substituted-Quinoxaline-Type PiperidineCompound 148, the endo isomer, and Substituted-Quinoxaline-TypePiperidine Compound 149, the exo isomer. More polar fraction 2 was alsotriturated with diethyl ether (50 mL) to provide 1.4 g ofSubstituted-Quinoxaline-Type Piperidine Compound 149 as a white solid.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 149,exo-4-(8-adamantan-1-yl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-oxo-3,4-dihydro-quinoxaline-2-carboxylicacid ethyl ester, was confirmed by nuclear Overhauser enhancementspectroscopy (“NOESY”) NMR experiments and MS.

Substituted-Quinoxaline-Type Piperidine Compound 149: ¹H NMR: δ_(H) (400MHz, CDCl₃): 8.37 (1H, bm), 7.91 (1H, dd, J=8.10, 1.56 Hz), 7.59 (1H,dt, 7.24, 1.59 Hz), 7.34 (1H, dt, J=8.04, 0.84 Hz), 5.91 (1H, m), 4.51(2H, q, J=7.1 Hz), 3.94 (2H, m), 2.61 (2H, dt, J=11.49, 8.30 Hz), 2.09(3H, m), 1.85-1.55 (19H, m), 1.44 (3H, t, J=7.13 Hz); MS: m/z=462.3[M+1]⁺ (Calc.: 462.3).

Re-chromatography of Fraction 1 with a silica gel column eluting with300:30:1:0.1 hexanes:EtOAc:MeOH:ammonia provided 440 mg ofSubstituted-Quinoxaline-Type Piperidine Compound 148 as a pale yellowsolid.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 148,endo-4-(8-adamantan-1-yl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-oxo-3,4-dihydro-quinoxaline-2-carboxylicacid ethyl ester, was confirmed by NOESY NMR and MS.

Substituted-Quinoxaline-Type Piperidine Compound 148: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.92 (1H, dd, J=8.02, 1.49 Hz), 7.61 (1H, t, J=8.15 Hz),7.52 (1H, d, J=8.15 Hz), 7.34 91H, dt, J=8.15, 1.49 Hz), 4.51 (2H, q,J=4.0 Hz), 3.87 (1H, m), 2.22 (2H, m), 2.05 (4H, m), 1.83 (4H, m),1.72-1.53 (15H, m), 1.44 (3H, t, J=4.0 Hz); MS: m/z=462.3 [M+1]⁺ (Calc.:462.3).

To a mixture of Substituted-Quinoxaline-Type Piperidine Compound 148(440 mg, 0.95 mmol) and tetrahydrofuran (10 mL) was added potassiumhydroxide (220 mg, 3.8 mmol) in water (1 mL) and the reaction mixturewas stirred at a temperature of about 25° C. for 3 h. TLC showed thatthe reaction was incomplete after this time so additional MeOH (5 mL)was added to form a homogeneous solution and the reaction mixture wasstirred at about 25° C. for an additional 2 h. The reaction mixture wasevaporated to dryness under reduced pressure to provide a residue. Theresidue was suspended in water (50 mL) and, using a pH meter, slowlyacidified to pH 5.5 with 1M HCl. The mixture was filtered. The filtercake was washed with acetone (50 mL) and dried under reduced pressure at70° C. for 18 h to provide 315 mg of a white solid (yield 78%). Thissolid (200 mg) was suspended in diethyl ether (5 mL) and 1M HCl (1 mL)was added. The resulting mixture was stirred at a temperature of about25° C. for 1 h then filtered. The filter cake was dried under reducedpressure at 70° C. for 18 h to provide 208 mg ofSubstituted-Quinoxaline-Type Piperidine Compound 130 as a pale yellowsolid.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 130,endo-4-(8-adamantan-1-yl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-oxo-3,4-dihydro-quinoxaline-2-carboxylicacid hydrochloride was confirmed using ¹H NMR and MS.

Substituted-Quinoxaline-Type Piperidine Compound 130: ¹H NMR: δ_(H) (500MHz, CD₃OD+DCl): 8.16 (1H, d, J=8.61 Hz), 7.99 (1H, dd, J=6.87, 1.16Hz), 7.82 (1H, dt, J=8.61, 1.16 Hz), 7.53 (1H, t, J=7.76 Hz), 6.15 (1H,m), 4.54 (2H, m), 2.96 (2H, m), 2.55 (2H, m), 2.37-2.25 (13H, m),1.81-1.74 (6H, m); MS: m/z=434.5 [M+l]⁺ (Calc.: 434.2).

Substituted-Quinoxaline-Type Piperidine Compound 149 (400 mg, 0.867mmol) was dissolved in MeOH (10 mL) with minimal heating then thesolution was quickly cooled to a temperature of about 25° C. Potassiumhydroxide (300 mg, 5.35 mmol) in water (2 mL) was added and the reactionmixture was stirred at a temperature of about 25° C. for 18 h. Thereaction mixture was evaporated to dryness under reduced pressure toprovide a residue. The residue was suspended in water (30 mL) and, usinga pH meter, slowly acidified to pH 5.5 with 1M HCl. The mixture wasfiltered. The filter cake was dried under reduced pressure at 50° C. for18 h to provide 165 mg of a white solid. The solid was suspended in drydiethyl ether (5 mL) and 2M HCl in diethyl ether (1 mL) was added. Theresulting mixture was stirred at a temperature of about 25° C. for 1 hthen filtered. The filter cake was dried under reduced pressure at 50°C. for 18 h to provide 160 mg of Substituted-Quinoxaline-Type PiperidineCompound 131 as a pale yellow solid.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 131,exo-4-(8-adamantan-1-yl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-oxo-3,4-dihydro-quinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and MS.

Substituted-Quinoxaline-Type Piperidine Compound 131: ¹H NMR: δ_(H) (400MHz, (CD₃)₂SO): 14.07 (1H, bs), 8.17 (1H, m), 7.85 (1H, dd, J=7.6, 1.28Hz), 7.69 (1H, t, J=8.28 Hz), 7.44 (1H, t, J=7.6 Hz), 5.29 (1H, bs),4.54 (2H, s), 3.11 (2H, t, J=12.93 Hz), 2.28-2.04 (13H, m), 1.94 (2H, d,J=11.67 Hz), 1.62 (6H, s); MS: m/z=434.5 [M+l]⁺ (Calc.: 434.5).

5.14 Example 14

The compound of formula EB, (bromomethyl)benzene (6.5 g, 38 mmol,Sigma-Aldrich), was added to a mixture of the compound of formula EA,8-methyl-8-azabicyclo[3.2.1]octan-3-one (5 g, 36 mmol, Sigma-Aldrich),in acetone (100 mL) over 30 min at a temperature of about 25° C. Theresulting reaction mixture was stirred at a temperature of about 25° C.for 1 h then at 38° C. for 2 h. Thereafter, the mixture was cooled to atemperature of about 25° C., filtered, and washed twice with hexanes (10mL for each wash) to provide 10 g of the compound of formula EC as whitesolid (yield 85%).

The compound of formula EC,8-benzyl-8-methyl-3-oxo-8-azoniabicyclo[3.2.1]octane bromide (5 g, 16.1mmol), was mixed with 40 mL of ethanol and 20 mL of water. Over 30 min,this mixture was added to a mixture of the compound of formula ED(cyclooctanamine, 2.0 g, 16 mmol, Sigma-Aldrich) and K₂CO₃ (0.2 g, 1.4mmol) in ethanol (150 mL) at 70° C. After 3 h at 70° C., the reactionmixture was cooled to a temperature of about 25° C. and concentratedunder reduced pressure. The residue was treated with water (50 mL) andextracted three times with CHCl₃ (100 mL for each extraction). Thecombined organic portions were washed with brine (50 mL) andconcentrated under reduced pressure to provide 3.5 g of the compound offormula EE (yield 92%).

Sodium triacetoxyborohydride (50 mmol) was added to a mixture of thecompound of formula EE, 8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-one (3g, 12.8 mmol), and 1,2-phenylenediamine (3 g, 27.8 mmol) in 100 mL ofCH₂Cl₂ at a temperature of about 25° C. Thereafter, 3 mL of acetic acidwas added. The resulting reaction mixture was stirred at a temperatureof about 25° C. for about 16 h. Thereafter, MeOH (2 mL) and water (25mL) were added and the mixture was neutralized with 28% aqueous ammoniato adjust the pH to about 8. The organic portion was separated, washedwith brine (10 mL), concentrated under reduced pressure, andchromatographed with a silica gel column eluted with 10:1:1EtOAc:MeOH:TEA to provide 2.8 g of a mixture of EF and EG as brown oil(yield 68%).

The identity of the compound of formula EF,N¹-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)benzene-1,2-diamine,was confirmed using TLC.

Compound EF: TLC (SiO₂) 100:7:1 EtOAc:MeOH:NH₄OH: Rf=0.6 with UVdetection, Dragendorffs reagent.

The identity of the compound of formula EG,N¹-((exo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)benzene-1,2-diamine,was confirmed using TLC.

Compound EG: TLC (SiO₂) 100:7:1 EtOAc:MeOH:NH₄OH: Rf=0.4 with UVdetection, Dragendorffs reagent.

A mixture of the above brown oil (0.3 g, of the compounds of formula EFand EG) in 20 mL of diethyl oxalate (Sigma-Aldrich) was heated at 140°C. for 16 h. After cooling to a temperature of about 25° C., thereaction mixture was diluted with EtOAc, washed with 2N aqueous NaOH (30mL), washed with brine (20 mL), concentrated under reduced pressure, andchromatographed with a silica gel column eluted with 5:5:0.5:0.5EtOAc:hexane:MeOH:TEA to provide 60 mg and 20 mg of the two compounds offormula EH and EI, respectively, each as a white solid (yield 18% and6%, respectively).

The identity of the compound of formula EH,1-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)quinoxaline-2,3(1H,4H)-dione (i.e., the endo isomer), was confirmed using ¹H NMR, LC/MSand TLC.

Compound EH: ¹H NMR: δ_(H) (400 MHz, (CD₃OD+CDCl₃)): 7.51 (1H, d, J=7.9Hz), 7.11-7.21 (m, 3H), 5.16-5.24 (m, 1H), 4.08 (br, 2H), 2.9 (br, 1H),2.56-2.64 (m, 2H), 2.06-2.26 (m, 6H), 1.72-1.96 (m, 6H), 1.32-1.62 (m,8H); LC/MS (100%, t_(r)=4.988 min): m/z=382.4 [M+H]⁺ (Calc: 381.5); TLC(SiO₂) 100:7:1 EtOAc:MeOH:NH₄OH: Rf=0.5 with UV detection, Dragendorffsreagent.

The identity of the compound of formula EI,1-((exo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)quinoxaline-2,3(1H,4H)-dione(i.e., the exo isomer), was confirmed using ¹H NMR, LC/MS and TLC.

Compound EI: ¹H NMR: δ_(H) (400 MHz, (CD₃OD+CDCl₃)): 7.62 (br, 1H),7.21-7.24 (m, 3H), 4.95 (br, 1H), 3.75 (br, 2H), 3.36 (br, 1H),2.91-2.98 (m, 2H), 2.06-2.16 (m, 2H), 1.42-1.96 (m, 18H); LC/MS (100%,t_(r)=4.718 min): m/z=382.2 [M+H]⁺ (Calc: 381.5); TLC (SiO₂) 100:7:1EtOAc:MeOH:NH₄OH: Rf=0.45 with UV detection, Dragendorffs reagent.

The compound of formula EH (191 mg, 0.500 mmol) was suspended in thionylchloride (0.8 mL, Sigma-Aldrich). A catalytic amount of DMF was addedand the reaction mixture was refluxed for 30 min. Thereafter, thereaction mixture was cooled to 0° C. and diethyl ether (5 mL) was added.A precipitate formed. The precipitate was filtered and washed withdiethyl ether to provide 196 mg of the hydrochloride ofSubstituted-Quinoxaline-Type Piperidine Compound 347 as a pale yellowsolid (yield 90%). Thereafter, this hydrochloride was suspended insaturated aqueous NaHCO₃ and extracted with CHCl₃ to provide the freeSubstituted-Quinoxaline-Type Piperidine Compound 347, i.e., the endoisomer.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 347,3-chloro-1-((endo8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)quinoxalin-2(1H)-one, wasconfirmed using ¹H NMR.

Substituted-Quinoxaline-Type Piperidine Compound 347: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.80 (1H, d, J=8.1 Hz), 7.60-7.54 (2H, m), 7.37-7.33 (1H,m), 5.17 (1H, br s), 3.67 (2H, br s), 2.34-2.22 (5H, m), 2.04-1.98 (2H,m), 1.89-1.36 (16H, m).

5.15 Example 15

TEA (1.2 mmol) and serine amide hydrochloride (i.e.,(S)-2-amino-3-hydroxypropanamide hydrochloride, 0.45 mmol,Sigma-Aldrich) were added to a mixture of the hydrochloride ofSubstituted-Quinoxaline-Type Piperidine Compound 347 (130 mg, 0.3 mmol)in N-methyl pyrrolidine (3 mL) at 25° C. The resulting reaction mixturewas stirred at 80° C. for 3 hr. After cooling to a temperature of about25° C. and quenching with water (3 mL), the mixture was extracted threetimes with EtOAc/water (50 mL for each extraction), washed three timeswith water (50 mL for each wash), dried (Na₂SO₄), and concentrated underreduced pressure to provide a yellow oil. The oil was chromatographedwith a silica gel column eluted with a gradient of from 95:5:0.5CHCl₃:MeOH:aqueous ammonia to 9:1:0.1 CHCl₃:MeOH:aqueous ammonia toprovide 42 mg of Substituted-Quinoxaline-Type Piperidine Compound 98 asa pale yellow amorphous solid (yield 30%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 98,(2S)-2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)-3-hydroxypropanamide,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 98: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.46-7.41 (3H, m), 7.28-7.15 (4H, m), 5.05 (1H, t, J=5.83Hz), 4.45-4.41 (1H, m), 3.85-3.64 (4H, m), 2.38-1.41 (23H, m); LC/MS(98%, t_(r)=1.24 min): m/z=468.2 [M+H]⁺ (Calc: 467.6).

5.16 Example 16

In a manner similar to Example 15, the followingSubstituted-Quinoxaline-Type Piperidine Compounds were prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 347.

Substituted-Quinoxaline-Type Piperidine Compound 143 was prepared byusing methyl piperidine-4-carboxylate (Sigma-Aldrich) in place of serineamide hydrochloride (yield 73%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 143,methyl1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)piperidine-4-carboxylate,was confirmed using ¹H NMR.

Substituted-Quinoxaline-Type Piperidine Compound 143: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.45-7.18 (4H, m), 5.19 (1H, s), 4.57 (2H, d, J=13.18Hz), 3.62 (5H, s), 3.04 (2H, t, J=11.15 Hz), 2.64 (1H, d, J=11.15 Hz),2.36 (1H, s), 2.19 (2H, s), 2.02-1.40 (24H, m).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound 99was prepared from Substituted-Quinoxaline-Type Piperidine Compound 143in a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 174 in Example 7 (yield 70%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 99,1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)piperidine-4-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 99: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 10.50 (1H, s), 7.84 (1H, d, J=8.11 Hz), 7.50 (1H, dd,J=7.60, 1.52 Hz), 7.26 (2H, ddd, J=20.78, 12.67, 5.32 Hz), 5.83 (1H, t,J=9.38 Hz), 4.61 (2H, d, J=13.18 Hz), 4.21 (3H, s), 3.10 (2H, t, J=11.41Hz), 2.93 (1H, s), 2.67-2.54 (3H, m), 1.88 (22H, m); LC/MS (100%,t_(r)=1.79 min): m/z=493.3 [M+H]⁺ (Calc: 492.7).

Substituted-Quinoxaline-Type Piperidine Compound 144 was prepared byusing glycine ethyl ester (i.e., ethyl 2-aminoacetate, Sigma-Aldrich) inplace of serine amide hydrochloride (yield 67%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 144,ethyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)acetate,was confirmed using MS.

Substituted-Quinoxaline-Type Piperidine Compound 144: MS: m/z=467.3[M+H]⁺ (Calc: 466.6).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound106 was prepared from Substituted-Quinoxaline-Type Piperidine Compound144 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield88%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 106,2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)aceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 106: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 10.25 (0.9H, s), 9.43 (0.1H, s), 7.85-7.77 (2H, m), 7.41(1H, dd, J=7.10, 2.03 Hz), 7.25 (2H, ddd, J=16.86, 9.25, 2.91 Hz), 5.81(0.9H, t, J=9.38 Hz), 5.15 (0.1H, s), 4.21 (2H, s), 4.06 (2H, d, J=6.08Hz), 2.93 (1H, s), 2.65 (2H, dt, J=17.07, 6.72 Hz), 2.40-1.39 (22H, m);LC/MS (100%, t_(r)=1.46 min): m/z=439.2 [M+H]⁺ (Calc: 438.6).

Substituted-Quinoxaline-Type Piperidine Compound 175 was prepared byusing methyl 2-(piperidin-4-yl)acetate (Sigma-Aldrich) in place ofserine amide hydrochloride (yield 89%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 175,methyl24144-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)piperidin-4-yl)acetate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 175: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.52 (1H, d, J=8.0 Hz), 7.37 (1H, d, J=8.0 Hz), 7.20 (2H,m), 5.20 (1H, br), 4.71 (2H, d, J=12.0 Hz), 3.69 (3H, s), 3.65 (2H, m),2.90 (2H, t, J=12.0 Hz), 2.40-1.90 (7H, m), 1.90-1.35 (22H, m); LC/MS:m/z=521 [M+H]⁺ (Calc: 520.3).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound176 was prepared from Substituted-Quinoxaline-Type Piperidine Compound175 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield76%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 176,2-(1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)piperidin-4-yl)aceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 176: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 12.1 (1H, m), 10.4 (0.9H, m), 9.52 (0.1H, m), 7.80 (1H,m), 7.43 (1H, m), 7.21 (2H, m), 5.80 (1H, m), 4.70 (2H, d, J=12.0 Hz),4.20 (2H, m), 2.92 (2H, t, J=12.0 Hz), 2.60 (2H, m), 2.40-1.23 (27H, m);LC/MS (100%, t_(r)=1.84 min): m/z=507 [M+H]⁺ (Calc: 506.3).

Substituted-Quinoxaline-Type Piperidine Compound 145 was prepared byusing the hydrochloride of methyl 2-(pyrrolidin-3-yl)acetate in place ofserine amide hydrochloride (yield 90%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 145,methyl2-(1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)pyrrolidin-3-yl)acetate,was confirmed using ¹H NMR.

Substituted-Quinoxaline-Type Piperidine Compound 145: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.31 (2H, dt, J=16.90, 6.84 Hz), 7.19-7.11 (2H, m), 5.12(1H, br), 3.80 (6H, m), 3.62 (3H, s), 2.35 (1H, s), 2.22-1.38 (23H, m).

Substituted-Quinoxaline-Type Piperidine Compound 114 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 145 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 71%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 114,2-(1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)pyrrolidin-3-yl)aceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 114: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.32 (2H, td, J=10.01, 3.72 Hz), 7.19-7.10 (2H, m), 5.17br), 4.22-3.03 (6H, br), 2.41 (4H, m), 2.25-1.37 (24H, m); LC/MS (99%,t_(r)=1.39 min): m/z=493.3 [M+H]⁺ (Calc: 492.7).

Substituted-Quinoxaline-Type Piperidine Compound 177 was prepared byusing methyl 3-aminopyrrolidine-3-carboxylate (Sigma-Aldrich) in placeof serine amide hydrochloride (yield 88%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 177,methyl3-amino-1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)pyrrolidine-3-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 177: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.45 (1H, m), 7.30 (1H, m), 7.13 (2H, m), 5.20 br),4.30-4.00 (4H, m), 3.77 (3H, s), 3.65 (2H, m), 2.50-2.00 (9H, m),1.90-1.36 (16H, m); LC/MS: m/z=508 [M+H]⁺ (Calc: 507.3).

Substituted-Quinoxaline-Type Piperidine Compound 178 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 177 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 72%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 178,3-amino-1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)pyrrolidine-3-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 178: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.90 (2H, br), 7.36 (2H, m), 7.17 (2H, m), 5.20 (1H, m),4.40-3.50 (6H, m), 2.50-1.30 (21H, m); LC/MS (100%, t_(r)=1.12 min):m/z=494 [M+H]⁺ (Calc: 493.3).

Substituted-Quinoxaline-Type Piperidine Compound 179 was prepared byusing methyl 4-(aminomethyl)benzoate hydrochloride (Sigma-Aldrich) inplace of serine amide hydrochloride (yield 36%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 179,methyl4-((4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)methyl)benzoate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 179: LC/MS: m/z=529[M+H]⁺ (Calc: 528).

Substituted-Quinoxaline-Type Piperidine Compound 180 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 179 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 28%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 180,4-((4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)methyl)benzoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxalinc-Type Piperidine Compound 180 ¹H NMR: δ_(H)(400MHz, DMSO-d₆): 10.24 (br, 1H), 8.67 (br, 1H), 7.88 (d, 2H, J=8.1 Hz),7.78-7.79 (m, 1H), 7.49 (d, 2H, J=8.1 Hz), 7.39-7.45 (m, 1H), 7.20-7.27(m, 2H), 5.76-5.80 (m, 1H), 4.71 (m, 2H), 4.18-4.26 (m, 2H), 2.95 (m,1H), 2.60-2.67 (m, 2H), 1.39-2.38 (m, 20H); LC/MS: m/z=515 [M+H]⁺ (Calc:514).

Substituted-Quinoxaline-Type Piperidine Compound 181 was prepared byusing methyl 4-amino-3-hydroxybutanoate (FB) in place of serine amidehydrochloride (yield 28%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 181,methyl4-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)-3-hydroxybutanoate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 181: LC/MS: m/z=497[M+H]⁺ (Calc: 496).

Substituted-Quinoxaline-Type Piperidine Compound 182 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 181 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 46%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 182,4-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)-3-hydroxybutanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 182: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.31-7.40 (m, 2H), 7.16-7.24 (m, 2H), 4.01 (m, 1H), 3.63(m, 2H), 3.29-3.41 (m, 2H), 1.39-2.37 (m, 25H); LC/MS: m/z=483 [M+H]⁺(Calc: 482).

The compound of formula FB was prepared as follows:

A mixture of 4-amino-3-hydroxybutanoic acid (FA, 1.00 g, 8.40 mmol,Sigma-Aldrich) and concentrated HCl (1 mL) in MeOH (20 mL) was refluxedfor 19 hr. The mixture was concentrated under reduced pressure toprovide 1.43 g of the compound of formula FB as a colorless oil (yield>98%).

Substituted-Quinoxaline-Type Piperidine Compound 183 was prepared byusing ethyl 5-(aminomethyl)furan-2-carboxylate (FE) in place of serineamide hydrochloride (yield 27%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 183,ethyl5-((4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)methyl)furan-2-carboxylate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 183: LC/MS: m/z=533[M+H]⁺ (Calc: 532).

Substituted-Quinoxaline-Type Piperidine Compound 184 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 183 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 37%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 184,5-((4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)methyl)furan-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 184: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 10.65 (br, 1H), 8.55 (br, 1H), 7.89-7.90 (m, 1H),7.52-7.53 (m, 1H), 7.24-7.27 (m, 2H), 7.14-7.24 (m, 1H), 6.56 (s, 1H),5.93-5.97 (m, 2H), 4.69 (m, 2H), 4.15-4.23 (m, 2H), 2.92 (m, 1H),2.62-2.67 (m, 2H), 2.18-2.34 (m, 6H), 1.27-1.96 (m, 14H); LC/MS: m/z=505[M+H]⁺ (Calc: 504).

The compound of formula FE was prepared as follows:

A mixture of ethyl 5-(chloromethyl)furan-2-carboxylate (EC, 1.00 g, 5.30mmol, Sigma-Aldrich), sodium azide (379.1 mg, 5.83 mmol, Sigma-Aldrich),and sodium iodate (catalytic amount, Sigma-Aldrich) in DMF at atemperature of about 25° C. was stirred for 24 h. The reaction mixturewas extracted with EtOAc/water. The organic portion was separated,washed with brine, dried (Na₂SO₄), filtered, and concentrated underreduced pressure to provide a residue. The residue was chromatographedwith a silica gel column eluted with 1:10 EtOAc:hexane to provide 950 mgof the compound of formula FD as a pale yellow solid (yield 92%).

The identity of the compound of formula FD, ethyl5-(azidomethyl)furan-2-carboxylate, was confirmed using ¹H NMR.

Compound FD: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.14 (d, 1H, J=3.4 Hz),6.47 (d, 1H, J=3.4 Hz), 4.39 (s, 2H), 4.37 (q, 2H, J=7.1 Hz), 1.38 (t,3H, J=7.1 Hz).

Under a hydrogen atmosphere, a mixture of the compound of formula FD(952 mg, 4.88 mmol), 20% palladium on carbon (100 mg, Sigma-Aldrich),and MeOH (10 mL) was stirred at a temperature of about 25° C. for 3.5hr. The Pd/C was filtered off, the mixture was washed with MeOH, and thefiltrate was concentrated under reduced pressure to provide 843 mg ofthe compound of formula FE as a brown oil (yield >98%).

Substituted-Quinoxaline-Type Piperidine Compound 185 was prepared byusing methyl 1,4-dioxa-8-azaspiro[4.5]decane-6-carboxylate (FI) in placeof serine amide hydrochloride (yield 67%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 185,methyl8-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane-6-carboxylate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 185: LC/MS: m/z=565[M+H]⁺ (Calc: 564).

Substituted-Quinoxaline-Type Piperidine Compound 186 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 185 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 27%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 186,8-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane-6-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 186: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 12.25 (br, 1H), 7.37-7.43 (m, 2H), 7.28-7.35 (m, 1H),7.19-7.21 (m, 1H), 5.05 (m, 1H), 4.30 (m, 1H), 4.09 (m, 1H), 3.92 (m,4H), 3.61 (m, 2H), 2.68-2.73 (m, 1H), 1.40-2.45 (m, 25H); LC/MS: m/z=551[M+H]⁺ (Calc: 550).

The compound of formula FI was prepared as follows:

After cooling a mixture of the compound of formula FF (methyl4-oxopiperidine-3-carboxylate hydrochloride, 5.00 g, 25.8 mmol,Sigma-Aldrich) and TMA (9.00 mL, 64.6 mmol, Sigma-Aldrich) in DCM (50mL) to a temperature of 0° C., benzyl carbonochloridate (4.85 g, 28.4mmol, Sigma-Aldrich) was added over a period of 10 min. After addition,the reaction mixture was stirred for lhr at a temperature of 0° C.,warmed to a temperature of about 25° C., and stirred for 1 hr more.Thereafter, the reaction mixture was extracted with DCM/water. Theorganic portion was separated, washed with 2N aqueous HCl, washed withsaturated NaHCO₃, washed with brine, dried (MgSO₄), filtered, andconcentrated under reduced pressure to provide 6.38 g of the compound offormula FG as a colorless oil (yield 85%).

The identity of the compound of formula FG, 1-benzyl 3-methyl4-oxopiperidine-1,3-dicarboxylate, was confirmed using ¹H NMR.

Compound FG: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 3.94-4.03 (m, 4H), 3.72 (s,3H), 3.16-3.21 (m, 1H), 3.02-3.09 (m, 2H), 2.85-2.92 (m, 1H), 2.66-2.68(m, 1H), 1.99-2.06 (m, 1H), 1.54-1.60 (m, 1H).

A reaction mixture of the compound of formula FG (6.38 g, 21.9 mmol),ethane-1,2-diol (3.66 mL, 65.7 mmol, Sigma-Aldrich), and4-methylbenzenesulfonic acid monohydrate (200 mg, Sigma-Aldrich) intoluene (150 mL) was refluxed for 21 hr. The reaction mixture wasextracted with diethyl ether:water. The organic portion was separated,washed with saturated NaHCO₃, washed with brine, dried (Na₂SO₄),filtered, and concentrated under reduced pressure to provide a residue.The residue was chromatographed with a silica gel column eluted with agradient of from 0%:100% EtOAc:n-hexane to 50%:50% EtOAc:n-hexane toprovide 2.48 g of the compound of formula FH as a colorless oil (yield34%).

The identity of the compound of formula FH, 8-benzyl 6-methyl1,4-dioxa-8-azaspiro[4.5]decane-6,8-dicarboxylate, was confirmed usingLC/MS.

Compound FM LC/MS: m/z=336 [M+H]⁺ (Calc: 335), 358 [M+Na]⁺ (Calc: 357).

Under a hydrogen atmosphere, a mixture of the compound of formula FH(2.48 g, 7.40 mmol), 20% palladium on carbon (200 mg), and MeOH (50 mL)was stirred at a temperature of about 25° C. for 3 hr. The Pd/C wasfiltered off, the mixture was washed with MeOH, and the filtrate wasconcentrated under reduced pressure to provide 1.50 g of the compound offormula H as a pale yellow oil (yield >98%).

The identity of the compound of formula FI was confirmed using ¹H NMR.

Compound FI: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 11.99 (s, 1H), 7.32-7.40(m, 5H), 5.16 (s, 2H), 4.14 (m, 2H), 3.78 (s, 3H), 3.63-3.66 (m, 2H),2.40 (m, 2H).

Substituted-Quinoxaline-Type Piperidine Compound 187 was prepared byusing methyl 4-hydroxypiperidine-4-carboxylate (Sigma-Aldrich) in placeof serine amide hydrochloride (yield 97%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 187,methyl1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)-4-hydroxypiperidine-4-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 187: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.43 (1H, d, J=8.0 Hz), 7.36 (1H, d, J=8.0 Hz), 7.29 (1H,t, J=8.0 Hz), 7.20 (1H, t, J=8.0 Hz), 5.56 (1H, s), 5.20 (1H, br), 4.42(2H, d, J=13.18 Hz), 3.65 (3H, s), 3.65-3.60 (2H, m), 3.36 (2H, m), 2.36(1H, m), 2.18 (2H, m), 2.02-1.30 (20H, m); LC/MS: m/z=523 [M+H]⁺ (Calc:522).

Substituted-Quinoxaline-Type Piperidine Compound 188 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 187 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 84%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 188,1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)-4-hydroxypiperidine-4-carboxylicacid, was confirmed using ¹H NMR and MS.

Substituted-Quinoxaline-Type Piperidine Compound 188: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 11.00-10.00 (1H, br) 7.74 (1H, d, J=8.0 Hz), 7.45 (1H, d,J=8.0 Hz), 7.26-7.22 (2H, m), 5.67 (1H, br), 5.90-5.10 (1H, br), 4.47(2H, d, J=12.6 Hz), 4.18 (2H, s), 3.34 (2H, m), 2.92 (1H, m), 2.54 (2H,m), 2.25 (6H, m), 2.01-1.40 (18H, m); LC/MS (100%, t_(r)=1.53 min):m/z=509 [M+H]⁺ (Calc: 508).

Substituted-Quinoxaline-Type Piperidine Compound 189 was prepared byusing 1,3,8-triazaspiro[4.5]decane-2,4-dione (Sigma-Aldrich) in place ofserine amide hydrochloride (yield 92%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 189,8-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione,was confirmed using ¹H NMR and MS.

Substituted-Quinoxaline-Type Piperidine Compound 189: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 10.71 (1H, s), 8.63 (1H, s), 7.45 (1H, d, J=7.6 Hz), 7.37(1H, m), 7.31 (1H, m), 7.21 (1H, m), 5.40-5.10 (1H, br), 4.49 (2H, s),3.62 (2H, s), 3.38 (2H, m), 2.70 (1H, s), 2.36 (1H, m), 2.19 (2H, m),2.10-1.30 (22H, m); LC/MS (100%, t_(r)=1.53 min): m/z=533 [M+H]⁺ (Calc:532).

Substituted-Quinoxaline-Type Piperidine Compound 190 was prepared byusing methyl 2-(2-aminoacetamido)acetate (Sigma-Aldrich) in place ofserine amide hydrochloride (yield 66%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 190,methyl2-(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)acetamido)acetate,was confirmed using ¹H NMR and MS.

Substituted-Quinoxaline-Type Piperidine Compound 190: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 8.35 (1H, m), 7.70 (1H, m), 7.39 (2H, m), 7.27 (1H, m),7.21 (1H, m), 5.00 (1H, br), 4.02 (2H, d, J=8.0 Hz), 3.65 (2H, m), 3.63(3H, s), 2.45-1.30 (19H, m); MS: m/z=510 [M+H]⁺ (Calc: 509).

Substituted-Quinoxaline-Type Piperidine Compound 191 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 190 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 51%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 191,2-(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)acetamido)aceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 191: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 8.21 (1H, m), 7.69 (1H, m), 7.58 (1H, m), 7.40 (1H, d,J=8.0 Hz), 7.26 (1H, m), 7.20 (1H, m), 5.40 (1H, br), 4.03 (2H, d, J=4.0Hz), 3.96 (2H, m), 3.75 (2H, d, J=4.0 Hz), 2.70-2.40 (3H, m), 2.30-1.30(20H, m); LC/MS (100%, t_(r)=1.31 min): m/z=496 [M+H]⁺ (Calc: 495).

Substituted-Quinoxaline-Type Piperidine Compound 192 was prepared byusing ethyl 4-aminopiperidine-4-carboxylate (Sigma-Aldrich) in place ofserine amide hydrochloride (yield 92%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 192,ethyl4-amino-1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)piperidine-4-carboxylate,was confirmed using ¹H NMR and MS.

Substituted-Quinoxaline-Type Piperidine Compound 192: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.43 (1H, d, J=8.0 Hz), 7.35 (1H, d, J=8.0 Hz), 7.28 (1H,t, J=8.0 Hz), 7.21 (1H, t, J=8.0 Hz), 5.20 (1H, br), 4.10 (4H, m), 3.62(4H, m), 2.35 (1H, m), 2.20 (2H, m), 2.10-1.40 (24H, m), 1.20 (3H, t,J=8.0 Hz); MS: m/z=536 [M+H]⁺ (Calc: 535).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound193 was prepared from Substituted-Quinoxaline-Type Piperidine Compound192 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield89%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 193,4-amino-1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)piperidine-4-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 193: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 10.75 (0.9H, m), 10.11 (0.1H, m), 8.82 (3H, s), 7.92(0.9H, d, J=8.62 Hz), 7.79 (0.1H, d, J=8.0 Hz), 7.53 (1H, d, J=8.0 Hz),7.30 (2H, m), 5.99-5.89 (0.9H, m), 5.10 (0.1H, m), 4.21-3.87 (8H, m),2.92 (1H, s), 2.66-2.55 (2H, m), 2.36-1.23 (24H, m); LC/MS (98%,t_(r)=1.09 min): m/z=508 [M+H]⁺ (Calc: 507).

To a mixture of Substituted-Quinoxaline-Type Piperidine Compound 193(130 mg, 0.211 mmol) and CH₂Cl₂ (4 mL) at 0° C. was added aceticanhydride (23.7 mg, 0.232 mmol, Sigma-Aldrich) and TEA (131 μL, 0.948mmol). The reaction mixture was stirred at 0° C. for 2 h. Afterconcentration under reduced pressure, the reaction mixture was dilutedwith water (2 mL) to precipitate a white solid. The precipitate wasfiltered and rinsed with water to provide 38 mg ofSubstituted-Quinoxaline-Type Piperidine Compound 194 as a white solid(yield 33%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 194,4-acetamido-1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)piperidine-4-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 194: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 8.15 (1H, s), 7.45 (2H, m), 7.31 (1H, t, J=8.0 Hz), 7.22(1H, t, J=8.0 Hz), 5.25 (1H, br), 4.36 (1H, d, J=12.0 Hz), 3.90-3.20(4H, m), 2.50 (1H, m), 2.30 (2H, m), 2.20-1.40 (24H, m), 1.87 (3H, s);LC/MS (100%, t_(r)=1.54 min): m/z=550 [M+H]⁺ (Calc: 549).

Substituted-Quinoxaline-Type Piperidine Compound 195 was prepared byusing methyl 3-hydroxypyrrolidine-3-carboxylate (Sigma-Aldrich) in placeof serine amide hydrochloride (yield 55%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 195,methyl1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)-3-hydroxypyrrolidine-3-carboxylate,was confirmed using ¹H NMR and MS.

Substituted-Quinoxaline-Type Piperidine Compound 195: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.36 (1H, d, J=8.0 Hz), 7.31 (1H, d, J=8.0 Hz), 7.20 (1H,t, J=8.0 Hz), 7.15 (1H, t, J=8.0 Hz), 5.88 (1H, s), 5.10 (1H, br), 4.20(2H, br), 3.72 (3H, s), 3.62 (2H, m), 3.35 (2H, m), 2.36 (1H, m),2.30-1.40 (24H, m); MS: m/z=509 [M+H]⁺ (Calc: 508).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound196 was prepared from Substituted-Quinoxaline-Type Piperidine Compound195 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield90%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 196,1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)-3-hydroxypyrrolidine-3-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 196: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 10.58 (0.9H, s), 9.80 (0.1H, s), 7.83 (0.9H, m), 7.74(0.1H, m), 7.65 (1H, s), 7.25 (2H, m), 5.85 (0.9H, m), 5.05 (0.1H, m),4.60-3.80 (6H, m), 2.98 (1H, m), 2.62 (2H, m), 2.40-1.30 (22H, m); LC/MS(100%, t_(r)=1.34 min): m/z=495 [M+H]⁺ (Calc: 494.5).

Substituted-Quinoxaline-Type Piperidine Compound 197 was prepared byusing methyl 2-amino-2-methylpropanoate hydrochloride (Sigma-Aldrich) inplace of serine amide hydrochloride (yield 30%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 197,2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)-2-methylpropanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 197: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.58 (1H, br), 7.52 (1H, s), 7.35 (1H, d, J=8.0 Hz), 7.22(2H, m), 5.40 (1H, br), 3.99 (2H, br), 2.65 (1H, m), 2.50 (2H, m),2.40-1.40 (20H, m), 1.61 (6H, s); LC/MS (100%, t_(r)=1.81 min): m/z=467[M+H]⁺ (Calc: 466.5).

Substituted-Quinoxaline-Type Piperidine Compound 198 was prepared byusing methyl 1-aminocyclohexanecarboxylate hydrochloride (Sigma-Aldrich)in place of serine amide hydrochloride (yield 35%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 198,methyl1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)cyclohexanecarboxylate,was confirmed using ¹H NMR and MS.

Substituted-Quinoxaline-Type Piperidine Compound 198: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.40 (1H, d, J=8.0 Hz), 7.26 (2H, m), 7.20 (1H, m), 7.05(1H, s), 5.00 (1H, br), 3.65 (2H, m), 3.56 (3H, s), 2.40-1.20 (33H, m);MS: m/z=521 [M+H]⁺ (Calc: 520).

Substituted-Quinoxaline-Type Piperidine Compound 199 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 198 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 81%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 199,1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)cyclohexanecarboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 199: ¹H NMR: δ_(H)(400MHz, DMSO-d₆): 7.70 (1H, br), 7.30 (1H, d, J=8.0 Hz), 7.25 (1H, t, J=8.0Hz), 7.21 (1H, t, J=8.0 Hz), 6.88 (1H, s), 5.60 (1H, br), 4.02 (2H, br),2.80-1.30 (31H, m); LC/MS (100%, t_(r)=2.04 min): m/z=507 [M+H]⁺ (Calc:506.5).

Substituted-Quinoxaline-Type Piperidine Compound 200 was prepared byusing ethyl 2-(2-oxopiperazin-1-yl)acetate (Sigma-Aldrich) in place ofserine amide hydrochloride (yield 89%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 200,ethyl2-(4-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)-2-oxopiperazin-1-yl)acetate,was confirmed using ¹H NMR and MS.

Substituted-Quinoxaline-Type Piperidine Compound 200: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.55 (1H, d, J=8.0 Hz), 7.41 (1H, d, J=8.0 Hz), 7.27 (1H,t, J=8.0 Hz), 7.21 (1H, t, J=8.0 Hz), 5.20 (1H, br), 4.59 (2H, s), 4.28(2H, m), 4.20 (2H, m), 3.67 (2H, m), 3.60 (2H, m), 2.40-2.00 (7H, m),1.90-1.40 (16H, m), 1.27 (3H, t, J=8.0 Hz); MS: m/z=550 [M+H]⁺ (Calc:549).

Substituted-Quinoxaline-Type Piperidine Compound 201 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 200 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 94%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 201,2-(4-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)-2-oxopiperazin-1-yl)aceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 201: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.54 (1H, m), 7.48 (1H, d, J=8.0 Hz), 7.34 (1H, t, J=8.0Hz), 7.24 (1H, t, J=8.0 Hz), 5.40 (1H, m), 4.44 (2H, s), 4.13 (2H, m),4.04 (2H, s), 3.85 (2H, m), 3.53 (2H, m), 2.67 (1H, m), 2.37 (2H, m),2.20-1.35 (20H, m); LC/MS (100%, t_(r)=1.52 min): m/z=522 [M+H]⁺ (Calc:521.5).

Substituted-Quinoxaline-Type Piperidine Compound 202 was prepared byusing (5)-methyl 1-(2-aminoacetyl)pyrrolidine-2-carboxylate(Sigma-Aldrich) in place of serine amide hydrochloride (yield 56%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 202,(S)-methyl1-(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)acetyl)pyrrolidine-2-carboxylate,was confirmed using ¹H NMR and MS.

Substituted-Quinoxaline-Type Piperidine Compound 202: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.51 (1H, d, J=8.0 Hz), 7.41 (1H, d, J=8.0 Hz), 7.20-7.05(3H, m), 5.20 (1H, br), 4.57 (1H, m), 4.29 (2H, d, J=8.0 Hz), 3.73 (2H,s), 3.65 (2H, m), 2.84 (3H, s), 2.40-1.40 (27H, m); MS: m/z=550 [M+H]⁺(Calc: 549).

Substituted-Quinoxaline-Type Piperidine Compound 203 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 202 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 77%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 203,1-(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)acetyl)pyrrolidine-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 203: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.69 (1H, br), 7.45 (2H, m), 7.23 (2H, m), 5.60 (1H, br),4.68 (0.2H, m), 4.30-3.80 (4.8H, m), 3.65 (2H, m), 2.90-1.30 (27H, m);LC/MS (100%, t_(r)=1.56 min): m/z=536 [M+H]⁺ (Calc: 535.5).

Substituted-Quinoxaline-Type Piperidine Compound 204 was prepared byusing (R)-4-tert-butyl 1-methyl 2-aminosuccinate (Sigma-Aldrich) inplace of serine amide hydrochloride (yield 28%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 204,(R)-4-tert-butyl 1-methyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)succinate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 204: LC/MS: m/z=567[M+H]⁺ (Calc: 567).

Substituted-Quinoxaline-Type Piperidine Compound 205 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 204 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 66%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 205,(R)-2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)succinicacid was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 205: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 1.35-2.37 (24H, m), 2.73 (1H, d, J=15.72 Hz), 3.62 (2H,s), 4.29 (1H, dd, J=10.65, 4.56 Hz), 5.11-5.42 (1H, m), 7.15-7.29 (2H,m), 7.36-7.44 (3H, m); LC/MS (98%, t_(r)=1.50 min): m/z=497 [M+H]⁺(Calc: 497).

Substituted-Quinoxaline-Type Piperidine Compound 206 was prepared byusing (9-methyl 2-amino-2-phenylacetate hydrochloride (Sigma-Aldrich) inplace of serine amide hydrochloride (yield 54%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 206,(9-methyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)-2-phenylacetate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 206: LC/MS: m/z=529[M+H]⁺ (Calc: 529).

Substituted-Quinoxaline-Type Piperidine Compound 207 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 206 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 15%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 207,(S)-2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)-2-phenylaceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 207: ¹H NMR: δ_(H)(400MHz, DMSO-d₆): 1.32-2.73 (22H, m), 2.94 (1H, s), 4.24 (2H, s), 5.14(0.1H, s), 5.61 (1H, d, J=6.59 Hz), 5.69 (0.9H, s), 7.21-7.54 (9H, m),7.73 (1H, dd, J=6.59, 2.03 Hz), 9.18 (0.1H, s), 9.94 (0.9H, s), 13.27(1H, s); LC/MS (98%, t_(r)=2.05 min): m/z=515 [M+H]⁺ (Calc: 515).

Substituted-Quinoxaline-Type Piperidine Compound 208 was prepared byusing (S)-methyl 2-amino-3-phenylpropanoate hydrochloride(Sigma-Aldrich) in place of serine amide hydrochloride (yield 86%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 208,(S)-methyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)-3-phenylpropanoate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 208: LC/MS: m/z=542[M+H]⁺ (Calc: 543).

Substituted-Quinoxaline-Type Piperidine Compound 209 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 208 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 33%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 209,(S)-2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)-3-phenylpropanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 209: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 1.32-2.40 (23H, m), 3.19-3.29 (2H, m), 3.75 (2H, s), 4.64(1H, dd, J=12.17, 7.1 Hz), 5.23 (1H, br s), 7.26-7.12 (7H, m), 7.49-7.31(3H, m); LC/MS (98%, t_(r)=2.04 min): m/z=529 [M+H]⁺ (Calc: 529).

Substituted-Quinoxaline-Type Piperidine Compound 210 was prepared byusing ethyl 1-(2-aminoethyl)piperidine-4-carboxylate (Sigma-Aldrich) inplace of serine amide hydrochloride (yield 77%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 210,ethyl14244-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)ethyl)piperidine-4-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 210: ¹H NMR: δ_(H) (400MHz, CDCl₃): 1.26 (3H, t, J=7.1 Hz), 1.35-2.43 (30H, m), 2.61 (2H, t,J=6.08 Hz), 2.92 (2H, d, J=11.15 Hz), 3.59 (2H, q, J=5.75 Hz), 3.67 (2H,br s), 4.14 (2H, q, J=6.93 Hz), 5.18 (1H, br s), 6.71 (1H, br s),7.15-7.22 (2H, m), 7.38-7.45 (1H, m), 7.49-7.55 (1H, m); LC/MS: m/z=564[M+H]⁺ (Calc: 564).

Substituted-Quinoxaline-Type Piperidine Compound 211 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 210 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 79%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 211,1-(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)ethyl)piperidine-4-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 211: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 1.32-2.56 (32H, m), 2.86 (2H, d, J=11.15 Hz), 3.46 (2H,d, J=5.58 Hz), 3.62 (2H, s), 5.03 (1H, br s), 7.15-7.25 (2H, m),7.31-7.42 (3H, m), 12.16 (1H, br s); LC/MS (t_(r)=0.84 min): m/z=536[M+H]⁺ (Calc: 536).

Substituted-Quinoxaline-Type Piperidine Compound 278 was prepared byusing (S)-ethyl 2-(pyrrolidin-3-ylamino)acetate (Sigma-Aldrich) in placeof serine amide hydrochloride (yield 80%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 278,ethyl2-((S)-1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)pyrrolidin-3-ylamino)acetate,was confirmed by ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 278: ¹H NMR: δ_(H)(CDCl₃): 7.44 (1H, m), 7.31 (1H, m), 7.13-7.12 (2H, m), 4.17 (2H, q,J=8.0 Hz), 4.15-3.60 (41-1, m), 3.65 (2H, m), 3.43 (2H, s), 3.40 (1H,m), 2.38-2.00 (7H, m), 1.86-1.40 (18H, m), 1.26 (3H, t, J=8.0 Hz);LC/MS: m/z=536 [M+H]⁺ (Calc: 535.7).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound279 was prepared from Substituted-Quinoxaline-Type Piperidine Compound278 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield47%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 279,2-((S)-1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)pyrrolidin-3-ylamino)aceticacid, was confirmed by ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 279: ¹H NMR: δ_(H)(DMSO-d₆): 10.78 (0.9H, d, J=7.6 Hz), 10.2 (0.1H, m), 9.71 (2H, s), 7.88(0.9H, d, J=7.6 Hz), 7.75 (0.1H, m), 7.53 (1H, s), 7.23 (2H, m), 5.92(1H, m), 4.22-3.91 (9H, m), 2.92 (1H, m), 2.65-2.60 (2H, m), 2.40-1.20(22H, m); LC/MS (97%, t_(r)=1.16 min): m/z=508 [M+H]⁺ (Calc: 507.6).

Substituted-Quinoxaline-Type Piperidine Compound 283 was prepared byusing (S)-ethyl 2-(methyl(pyrrolidin-3-yl)amino)acetate (Sigma-Aldrich)in place of serine amide hydrochloride (yield 97%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 283,ethyl2-(((S)-1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)pyrrolidin-3-yl)(methyl)amino)acetate,was confirmed by ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 283: ¹H NMR: δ_(H)(CDCl₃): 7.44 (1H, m), 7.33 (1H, m), 7.13 (2H, m), 5.30 (1H, br), 4.20(2H, q, J=8.0 Hz), 3.65 (2H, s), 3.39 (4H, m), 2.49 (3H, s), 2.40-1.40(27H, m) 1.38 (3H, t, J=8.0 Hz); LC/MS: m/z=550 [M+H]⁺ (Calc: 549.7).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound284 was prepared from Substituted-Quinoxaline-Type Piperidine Compound283 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield98%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 284,2-(((S)-1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)pyrrolidin-3-yl)(methyl)amino)aceticacid, was confirmed by ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 284: ¹H NMR: δ_(H)(DMSO-d₆): 11.00 (1H, br), 10.79 (0.9H, m), 10.2 (0.1H, m), 7.88 (0.9H,d, J=7.6 Hz), 7.70 (0.1H, m), 7.50 (1H, d, J=7.6 Hz), 7.22 (2H, m), 5.93(1H, s), 4.40-3.60 (7H, m), 2.93 (3H, s), 2.70-1.40 (27H, m); LC/MS(99%, t_(r)=1.13 min); LC/MS: m/z=522 [M+H]⁺ (Calc: 521.6).

Substituted-Quinoxaline-Type Piperidine Compound 373 was prepared byusing ethyl 2-(piperazin-1-yl)acetate (Sigma-Aldrich) in place of serineamide hydrochloride (yield 81%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 373,ethyl24444-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)piperazin-1-yl)acetate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 373: ¹H NMR: δ_(H)(DMSO-d₆): 1.19 (3H, t, J=7.6 Hz), 1.32-2.40 (23H, m), 2.64 (4H, t,J=4.56 Hz), 3.27 (2H, s), 3.62 (2H, br s), 3.79 (4H, br s), 4.09 (2H, q,J=7.1 Hz), 7.20 (1H, t, J=7.35 Hz), 7.31 (1H, t, J=7.1 Hz), 7.37 (1H, d,J=8.62 Hz), 7.45 (1H, d, J=4.56 Hz); LC/MS: m/z=536 [M+H]⁺ (Calc: 536).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound337 was prepared from Substituted-Quinoxaline-Type Piperidine Compound373 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield70%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 337,2-(4-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)piperazin-1-yl)aceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 337: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 1.31-2.35 (22H, m), 2.61 (2H, dd, J=20.78, 11.66 Hz),2.93 (1H, s), 3.01 (4H, s), 3.59 (2H, s), 3.95 (4H, s), 4.21 (2H, s),5.10 (0.1H, s), 5.83-5.96 (0.9H, m), 7.22-7.36 (2H, m), 7.48 (1H, dd,J=7.60, 1.52 Hz), 7.78 (0.1H, d, J=8.62 Hz), 7.90 (0.9H, d, J=8.11 Hz),9.84 (0.1H, s), 10.64 (0.9H, s), 12.18 (1H, br s); LC/MS (t_(r)=1.10min): m/z=508 [M+H]⁺ (Calc: 508).

Substituted-Quinoxaline-Type Piperidine Compound 212 was prepared byusing piperazin-2-one in place of serine amide hydrochloride (yield99%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 212,1-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-(3-oxopiperazin-1-yl)quinoxalin-2(1H)-one,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 212: ¹H NMR: δ_(H) (400MHz, CDCl₃): 1.35-2.42 (23H, m), 3.57 (2H, s), 3.66 (2H, s), 4.17 (2H,s), 4.52 (2H, s), 5.19 (1H, br s), 6.53 (1H, br s), 7.18-7.32 (2H, m),7.41 (1H, d, J=8.11 Hz), 7.56 (1H, d, J=8.11 Hz); LC/MS (t_(r)=1.66min): m/z=464 [M+H]⁺ (Calc: 464).

Substituted-Quinoxaline-Type Piperidine Compound 213 was prepared byusing tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate inplace of serine amide hydrochloride (yield 98%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 213,tert-butyl5-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 213: ¹H NMR: 5 (400MHz, DMSO) 7.34 (1H, d, J=8.0 Hz), 7.28 (1H, d, J=8.0 Hz), 7.18 (1H, t,J=8.0 Hz), 7.15 (1H, d, J=8.0 Hz), 5.10 (1H, br), 4.08 (2H, br),3.80-3.50 (4H, m), 3.18 (2H, m), 2.80 (2H, m), 2.34 (1H, m), 2.16 (2H,m), 2.10-1.45 (22H, m), 1.39 (9H, s); LC/MS: m/z=576 [M+H]⁺ (Calc:575.3).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound214 was prepared from Substituted-Quinoxaline-Type Piperidine Compound213 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 5 in Example 7 (yield99%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 214,1-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinoxalin-2(1H)-one,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 214: ¹H NMR: δ_(H) (400MHz, DMSO): 10.73 (1H, m), 9.69 (1H, m), 9.62 (1H, m), 7.88 (1H, d,J=8.0 Hz), 7.65 (1H, d, J=8.0 Hz), 7.28 (2H, m), 5.88 (1H, m), 4.22 (2H,m), 4.20-3.90 (4H, m), 3.45 (2H, m), 3.15 (4H, m), 2.90 (1H, m), 2.60(2H, m), 2.40-1.30 (20H, m); LC/MS: m/z=476 [M+H]⁺ (Calc: 475.3).

At a temperature of about 25° C., ethyl 2-bromoacetate (55 mg, 0.328mmol, Sigma-Aldrich) and K₂CO₃ (151 mg, 1.094 mmol) were added to amixture of Substituted-Quinoxaline-Type Piperidine Compound 214 (150 mg,0.273 mmol) in DMF (4 mL). The resulting reaction mixture was stirred atabout 25° C. for 3 h. The reaction mixture was diluted with water (5 mL)and extracted three times with EtOAc (10 mL for each extraction). Theorganic portions were combined, washed with saturated aqueous NaCl (10mL), dried (MgSO₄), and concentrated under reduced pressure to provide aresidue. The residue was chromatographed with a silica gel column elutedwith a gradient of from 100%:0% CHCl₃:MeOH to 90%:10% CHCl₃:MeOH toprovide 135 mg of Substituted-Quinoxaline-Type Piperidine Compound 215as a white amorphous solid (yield 88%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 215,ethyl2-(5-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)acetate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 215: ¹H NMR: δ_(H) (400MHz, DMSO): 10.40 (1H, m), 7.73 (1H, m), 7.39 (1H, d, J=8.0 Hz), 7.20(2H, m), 5.70 (1H, m), 4.30-3.80 (8H, m), 3.20-2.80 (6H, m), 2.80-1.30(23H, m); LC/MS: m/z=562 [M+H]⁺ (Calc: 561.3).

Substituted-Quinoxaline-Type Piperidine Compound 216 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 215 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 70%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 216,2-(5-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)aceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 216: ¹H NMR: δ_(H) (400MHz, DMSO): 10.40 (1H, m), 7.73 (1H, m), 7.39 (1H, d, J=8.0 Hz), 7.20(2H, m), 5.70 (1H, m), 4.30-3.80 (8H, m), 3.20-2.80 (6H, m), 2.80-1.30(23H, m); LC/MS (100%, t_(r)=1.20 min): m/z=534 [M+H]⁺ (Calc: 533.5).

In a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 216, Substituted-Quinoxaline-Type PiperidineCompound 226 was prepared by using tert-butyl 2-aminoethylcarbamate inplace of tert-butyl-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(yield 17% for four steps).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 223,tert-butyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)ethylcarbamate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 223: ¹H NMR: δ_(H)(400MHz, DMSO-d₆): 1.36-2.38 (32H, m), 3.18 (2H, q, J=5.91 Hz), 3.42 (2H, q,J=5.91 Hz), 3.63 (2H, br s), 5.06 (1H, br s), 6.91-6.94 (1H, m),7.16-7.24 (2H, m), 7.38 (2H, t, J=6.08 Hz), 7.56 (1H, s); LC/MS: m/z=524[M+H]⁺ (Calc: 524).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 224,3-(2-aminoethylamino)-1-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)quinoxalin-2(1H)-one,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 224: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 1.41-2.37 (24H, m), 2.75 (2H, t, J=6.34 Hz), 3.36 (2H, t,J=6.08 Hz), 3.57 (2H, s), 3.62 (2H, br s), 5.08 (1H, br s), 7.17-7.21(2H, m), 7.36-7.39 (2H, m), 7.50-7.52 (1H, m); LC/MS: m/z=424 [M+H]⁺(Calc: 424).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 225,ethyl2-(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)ethylamino)acetate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 225: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 1.19 (3H, t, J=6.84 Hz), 1.98 (22H, dt, J=188.24, 72.62Hz), 2.74 (2H, d, J=6.59 Hz), 2.77-2.78 (1H, m), 2.90 (2H, d, J=6.59Hz), 3.37 (2H, d, J=6.59 Hz), 3.63 (2H, s), 4.04-4.11 (2H, m), 5.08 (1H,s), 7.16-7.25 (2H, m), 7.38 (2H, dd, J=12.67, 8.62 Hz), 7.49 (1H, d,J=5.07 Hz), 7.96 (1H, d, J=5.58 Hz); LC/MS: m/z=255.5 [M+2H]²⁺ (Calc:255.5).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 226,2-(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)ethylamino)aceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 226: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 1.98 (23H, dtt, J=301.97, 81.62, 34.22 Hz), 3.14 (2H, d,J=5.07 Hz), 3.43 (2H, s), 3.62 (2H, d, J=5.07 Hz), 4.17 (2H, s), 5.61(1H, br s), 7.12 (1H, s), 7.20 (1H, d, J=7.6 Hz), 7.43 (1H, d, J=7.6Hz), 7.57 (1H, s), 7.94 (1H, s), 10.72 (1H, brs); LC/MS (t_(r)=1.01min): m/z=482 [M+H]⁺ (Calc: 481.6).

To a mixture of Substituted-Quinoxaline-Type Piperidine Compound 224 (38mg, 0.090 mmol) and DMF (1 mL) at a temperature of about 25° C. wasadded a solution of ethyl 2-bromoacetate (0.187 mL, 0.188 mmol) in MeCN(1 mL). The resulting reaction mixture was stirred at about 25° C. for 2h. The reaction mixture was diluted with water and extracted twice withEtOAc (20 mL for each extraction). The organic portions were combined,washed with brine, dried (MgSO₄), filtrated, and concentrated underreduced pressure to provide a residue. The residue was chromatographedwith a silica gel column (Yamazen, S (amino)) eluted with a gradient offrom 95%:5% hexanes:EtOAc to 75%:25% hexanes:EtOAc to provide 28.8 mg ofSubstituted-Quinoxaline-Type Piperidine Compound 227 as a yellow solid(yield 54%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 227,diethyl2,2′-(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)ethylazanediyl)diacetate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 227: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 1.17 (3H, t, J=7.1 Hz), 1.18 (3H, t, J=7.1 Hz), 1.31-2.42(23H, m), 2.91 (2H, s), 3.42 (2H, s), 3.58 (4H, d, J=3.55 Hz), 3.64 (2H,s), 4.02-4.11 (4H, m), 5.05 (1H, br s), 7.15-7.26 (2H, m), 7.34-7.40(2H, m), 7.42-7.48 (1H, m); LC/MS: m/z=298.5 [M+2H]²⁺ (Calc: 298.5).

Substituted-Quinoxaline-Type Piperidine Compound 228 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 227 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 56%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 228,2,2′-(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)ethylazanediyl)diaceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 228: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 1.31-2.81 (22H, m), 2.88-2.98 (2H, m), 3.40-3.47 (2H, m),3.51 (4H, s), 4.24 (2H, s), 5.11 (0.1H, s), 5.65 (0.9H, s), 7.19-7.26(2H, m), 7.38-7.43 (1H, m), 7.58-7.64 (2H, m), 7.67-7.75 (2H, br m),9.22 (0.1H, s), 9.95 (0.9H, s), 12.33 (1H, br s); LC/MS (t_(r)=1.36min): m/z=540 [M+H]⁺ (Calc: 540).

Substituted-Quinoxaline-Type Piperidine Compound 217 was prepared byusing (S)-tert-butyl 2-(2-aminoethylamino)-3-hydroxypropanoate (FM) inplace of serine amide hydrochloride (yield 99%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 217,(S)-tert-butyl2-(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)ethylamino)-3-hydroxypropanoate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 217: ¹H NMR: δ_(H)(CDCl₃): 1.36-2.42 (32H, m), 2.77-2.85 (1H, m), 2.93 (1H, br s),3.02-3.10 (1H, m), 3.33 (1H, dd, J=6.59, 4.56 Hz), 3.52-3.58 (2H, m),3.62-3.81 (4H, m), 5.15 (1H, br s), 6.64 (1H, br s), 7.17-7.23 (2H, m),7.39-7.45 (1H, m), 7.50-7.56 (1H, m); LC/MS: m/z=568 [M+H]⁺ (Calc: 568).

Under a nitrogen atmosphere, to a mixture ofSubstituted-Quinoxaline-Type Piperidine Compound 217 (260 mg, 0.458mmol) and dioxane (6 mL) at a temperature of about 25° C. was added 4NHCl in dioxane (2 mL, 8.00 mmol). The resulting reaction mixture waswarmed to 50° C. and stirred for 4 h. The mixture was filtrated with aHirsch funnel, washed with dioxane, dried under reduced pressure for 8 hat 85° C., then chromatographed by a reverse phase chromatographyapparatus (Gilson Inc, Middletown Wis.). The collected fraction wasdried under reduced pressure to provide 112 mg ofSubstituted-Quinoxaline-Type Piperidine Compound 218 (yield 48%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 218,2-(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)ethylamino)-3-hydroxypropanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 218: ¹H NMR: δ_(H)(DMSO-d₆): 1.29-2.40 (21H, m), 2.53-2.73 (2H, m), 2.90 (1H, br s), 3.22(3H, t, J=5.32 Hz), 3.62-3.75 (3H, m), 3.84 (2H, ddd, J=25.73, 11.79,3.93 Hz), 4.16 (2H, d, J=24.33 Hz), 5.12 (0.1H, br s), 5.78 (0.9H, brs), 7.12-7.23 (2H, m), 7.44 (1H, d, J=7.1 Hz), 7.68-7.78 (1H, m), 8.00(1H, t, J=5.58 Hz), 9.84 (0.1H, br s), 10.76 (0.9H, br s); LC/MS(t_(r)=1.09 min): m/z=512 [M+H]⁺ (Calc: 512).

The compound of formula FM was prepared as follows:

Under a nitrogen atmosphere, to a mixture of benzyl2-hydroxyethylcarbamate (FJ, 1000 mg, 5.12 mmol) and CH₂Cl₂ (13 mL) at atemperature of from −20° C. to −17° C. were added DIEA (2340 μL, 13.40mmol) and trifluoromethanesulfonic anhydride (909 μL, 5.38 mmol). Theresulting reaction mixture was stirred for 1 h at a temperature of −20°C. Thereafter, (R)-tert-butyl 3-amino-4-hydroxybutanoate (FK, 1239 mg,7.68 mmol, Sigma-Aldrich) in CH₂Cl₂ (5 mL) was slowly added. Theresulting reaction mixture was stirred for 4 h as its temperature warmedfrom −20° C. to −5° C. Thereafter, the reaction mixture was diluted withsaturated aqueous NaHCO₃ then extracted 3 times with CHCl₃ (30 mL foreach extraction). The organic portions were combined, washed with brine,dried (MgSO₄), filtered, and concentrated under reduced pressure. Theresidue was chromatographed with an amino-silica gel column (YamazenCorp. W091-01) eluted with a gradient of from 20%:80% EtOAc:n-hexane to80%:20% EtOAc:n-hexane to provide 921 mg of the compound of formula FLas a yellow oil (yield 53%).

The identity of the compound of formula FL, (S)-tert-butyl2-(2-(benzyloxycarbonylamino)ethylamino)-3-hydroxypropanoate, wasconfirmed using ¹H NMR and LC/MS.

Compound FL: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 1.46 (9H, s), 2.61-2.70(1H, m), 2.82-2.91 (1H, m), 3.16-3.27 (2H, m), 3.30-3.42 (1H, m), 3.54(1H, dd, J=10.90, 6.84 Hz), 3.74 (1H, dd, J=10.65, 4.56 Hz), 5.10 (2H,s), 5.21 (1H, br s), 7.31-7.37 (5H, m); LC/MS: m/z=339 [M+H]⁺ (Calc:339).

Under a hydrogen atmosphere, a mixture of the compound of formula FL(906 mg, 2.68 mmol), 10% palladium on carbon, 50% wet (285 mg, 0.134mmol), and MeOH (10 mL) was stirred at a temperature of about 25° C. for3 h. The Pd/C was filtered off, the mixture was washed with MeOH, andthe filtrate was concentrated under reduced pressure to provide 651 mgof the compound of formula FM as a pale yellow solid (yield >98%).

The identity of the compound of formula FM, (S)-tert-butyl2-(2-aminoethylamino)-3-hydroxypropanoate, was confirmed using ¹H NMRand LC/MS.

Compound FM: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 1.47 (9H, s), 2.55-2.64(1H, m), 2.78-2.86 (3H, m), 3.27 (1H, dd, J=6.84, 4.31 Hz), 3.55 (1H,dd, J=10.65, 6.59 Hz), 3.77 (1H, dd, J=10.90, 4.31 Hz); LC/MS: m/z=205[M+H]⁺ (Calc: 205).

Substituted-Quinoxaline-Type Piperidine Compound 219 was prepared byusing tert-butyl 2-(2-aminoethylamino)acetate (Sigma-Aldrich) in placeof serine amide hydrochloride (yield 86%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 219,tert-butyl2-(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)ethylamino)acetate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 219: ¹H NMR: δ_(H)(CDCl₃): 1.35-1.89 (2H, m), 1.98-2.03 (1H, m), 2.13-2.42 (4H, m), 2.91(2H, t, J=5.83 Hz), 3.34 (2H, s), 3.61 (2H, q, J=5.91 Hz), 3.66 (2H, brs), 5.13 (1H, br s), 6.69 (1H, s), 7.16-7.22 (2H, m), 7.38-7.44 (1H, m),7.49-7.55 (1H, m); LC/MS: m/z=538 [M+H]⁺ (Calc: 538).

To a mixture of Substituted-Quinoxaline-Type Piperidine Compound 219(305 mg, 0.567 mmol) and MeCN (5 mL) at a temperature of about 25° C.was added 2-bromoacetamide (86 mg, 0.624 mmol, Sigma-Aldrich) and K₂CO₃(86 mg, 0.624 mmol). The resulting reaction mixture was warmed to 60° C.and stirred for 3 h. The reaction mixture was diluted with water andextracted twice with CHCl₃ (20 mL for each extraction). The organicportions were combined, washed with brine, dried (MgSO₄), filtrated, andconcentrated under reduced pressure to provide a residue. The residuewas chromatographed with a silica gel column (Yamazen, M (amino)) elutedwith a gradient of from 60%:40% hexanes:EtOAc to 0%:100% hexanes:EtOActo provide a fractions. The fractions were combined and concentratedunder reduced pressure to provide a colorless amorphous solid which waschromatographed with a silica gel column (Yamazen, M (amino)) elutedwith a gradient of from 99%:1% CHCl₃:(MeOH:NH₃=10:1) to 90%:10%CHCl₃:(MeOH:NH₃=10:1) to provide 252 mg of Substituted-Quinoxaline-TypePiperidine Compound 220 (yield 75%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 220,text-butyl2-((2-amino-2-oxoethyl)(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)ethyl)amino)acetate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 220: ¹H NMR: δ_(H)(CDCl₃): 1.35-2.41 (32H, m), 2.96 (2H, t, J=4.82 Hz), 3.33 (2H, s), 3.38(2H, s), 3.57-3.63 (2H, m), 3.66 (2H, br s), 5.18 (1H, br s), 5.40 (1H,br s), 6.65 (1H, br s), 7.17-7.23 (2H, m), 7.38-7.44 (1H, m), 7.47-7.53(1H, m), 7.55 (1H, br s); LC/MS: m/z=595 [M+H]⁺ (Calc: 595).

Substituted-Quinoxaline-Type Piperidine Compound 221 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 220 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound218 (yield 96%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 221,2-((2-amino-2-oxoethyl)(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)ethyl)amino)aceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 221: ¹H NMR: δ_(H)(CD₃OD): 1.35-2.43 (20H, m), 2.61-2.74 (2H, m), 2.95-3.12 (3H, m),3.34-3.71 (6H, m), 4.17 (2H, br s), 5.45 (1H, br s), 7.25-7.15 (2H, m),7.46 (1H, d, J=7.6 Hz), 7.58 (1H, d, J=8.11 Hz); LC/MS (t_(r)=1.06 min):m/z=539 [M+H]⁺ (Calc: 539).

Substituted-Quinoxaline-Type Piperidine Compound 374, methyl5-((4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)methyl)-2-hydroxybenzoate,was prepared by using methyl 5-(aminomethyl)-2-hydroxybenzoate (FT) inplace of serine amide hydrochloride. Substituted-Quinoxaline-TypePiperidine Compound 211 was prepared from Substituted-Quinoxaline-TypePiperidine Compound 374 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 111 in Example 5 (yield9% for two steps).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 330,5-((4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)methyl)-2-hydroxybenzoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 330: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 13.97 (br, 1H), 11.16 (s, 1H), 10.49 (s, 1H), 8.51 (br,1H), 7.78-7.91 (m, 2H), 7.59-7.62 (m, 1H), 7.49 (m, 1H), 7.23-7.25 (m,2H), 6.90-6.92 (m, 1H), 5.85-5.90 (m, 1H), 4.45-4.57 (m, 2H), 4.19-4.36(m, 2H), 2.92 (m, 1H), 2.59-2.64 (m, 2H), 1.16-2.34 (m, 20H); LC/MS:m/z=568 [M+H]⁺ (Calc: 567).

Methyl 5-(aminomethyl)-2-hydroxybenzoate (FT) was prepared as follows:

A reaction mixture of 5-formyl-2-hydroxybenzoic acid (FN, 5.00 g, 30.1mmol, Sigma-Aldrich), concentrated H₂SO₄ (2.00 mL), and MeOH (50 mL) wasstirred at reflux for 24 h. Thereafter, the mixture was concentratedunder reduced pressure to provide 5.36 g of the compound of formula FO,methyl 5-formyl-2-hydroxybenzoate, as colorless oil (yield 99%). Areaction mixture of the compound of formula FO (5.36 g, 29.7 mmol), thecompound of formula EB (3.89 mL, 32.8 mmol), K₂CO₃ (4.93 g, 35.7 mmol),and acetone (150 mL) was stirred at reflux for 22 h. Thereafter, themixture was concentrated under reduced pressure to provide 4.92 g of thecompound of formula FP, methyl 2-(benzyloxy)-5-formylbenzoate, as awhite solid (yield 61%). A reaction mixture of the compound of formulaFP (4.40 g, 16.3 mmol), sodium tetrahydroborate (738 mg, 19.5 mmol), andTHF (50 mL) was stirred for 1 h at a temperature of 0° C., warmed to atemperature of about 25° C., and stirred for 1 h more. Thereafter, thereaction mixture was partitioned between EtOAc and water. The organicportion was separated, washed with saturated aqueous NaHCO₃, washed withbrine, dried (Na₂SO₄), filtered, concentrated under reduced pressure,and chromatographed with a silica gel column eluted with a gradient offrom 100%:0% hexane:EtOAc to 50%:50% hexane:EtOAc to provide 3.98 g ofthe compound of formula FQ, methyl2-(benzyloxy)-5-(hydroxymethyl)benzoate, as a colorless oil (yield 90%).

A reaction mixture of the compound of formula FQ, (3.98 g, 14.6 mmol),phosphorus tribromide (687 mL, 7.31 mmol, Sigma-Aldrich), and diethylether (100 mL) was stirred for 1 h at a temperature of 0° C. Thereafter,the reaction mixture was partitioned between diethyl ether and water.The organic portion was separated, washed with saturated aqueous NaHCO₃,washed with brine, dried (Na₂SO₄), filtered, concentrated under reducedpressure to provide 4.90 g of the compound of formula FR, methyl2-(benzyloxy)-5-(bromomethyl)benzoate, as a white solid (yield >99%). Areaction mixture of the compound of formula FR (4.90 g, 14.6 mmol),sodium azide (1.05 g, 16.1 mmol), potassium iodide (catalytic amount,Sigma-Aldrich), and DMF (100 mL) was stirred for 20 h at a temperatureof about 25° C. Thereafter, the reaction mixture was partitioned betweenEtOAc and water. The organic portion was separated, washed withsaturated aqueous NaHCO₃, washed with brine, dried (Na₂SO₄), filtered,concentrated under reduced pressure, and chromatographed with a silicagel column eluted with a gradient of from 100%:0% hexane:EtOAc to50%:50% hexane:EtOAc to provide 2.82 g of the compound of formula FS,methyl 5-(azidomethyl)-2-(benzyloxy)benzoate, as a colorless oil (yield65%). Under a hydrogen atmosphere, a mixture of the compound of formulaFS (1.28 g, 4.30 mmol), 20% palladium on carbon by weight (120 mg), MeOH(5 mL), and EtOAc (10 mL) was stirred at a temperature of about 25° C.for 5 h. The Pd/C was filtered off with a CELITE pad, the mixture waswashed with EtOAc, then concentrated under reduced pressure to provide afirst residue. The first residue was suspended in MeOH, the insolublesolid filtered off, and the filtrate concentrated under reduced pressureto provide a second residue. The second residue was washed with EtOAc toprovide 438 mg of the compound of formula FT as a brown solid (yield56%).

Substituted-Quinoxaline-Type Piperidine Compound 326 was prepared byusing (3S,4S)-diethyl 1-(2-aminoethyl)pyrrolidine-3,4-dicarboxylate (FX)in place of serine amide hydrochloride (yield 75%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 326,(3S,4S)-diethyl1-(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)ethyl)pyrrolidine-3,4-dicarboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 326: ¹H NMR: δ_(H) (400MHz, CD₃OD): 7.51 (m, 2H), 7.25 (m, 2H), 5.10 (s, br, 1H), 4.12 (dd,4H), 3.7 (s, br, 2H), 3.60 (m, 1H), 3.42 (m, 2H), 2.89 (m, 2H), 2.75 (m,2H), 2.55 (s, br, 1H), 2.38-1.35 (m, 22H), 1.25 (t, 6H); LC/MS: m/z=566[M+H]⁺ (Calc: 565).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound327 was prepared from Substituted-Quinoxaline-Type Piperidine Compound326 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield60%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 327,(3S,4S)-1-(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)ethyl)pyrrolidine-3,4-dicarboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 327: ¹H NMR: δ_(H) (400MHz, CD₃OD): 7.36-7.38 (m, 2H), 7.12-7.06 (m, 2H), 5.27-5.09 (s, br.1H), 3.60 (s, br, 2H), 3.57-3.45 (m, 2H), 2.89 (t, J=8.8 Hz, 2H),2.82-2.78 (m, 2H), 2.72-2.53 (m, 3H), 2.46-2.36 (s, br, 1H), 2.27-1.36(m, 22H); LC/MS: m/z=566 [M+H]⁺ (Calc: 565).

The sodium salt of Substituted-Quinoxaline-Type Piperidine Compound 327was prepared as follows. To a mixture of Substituted-Quinoxaline-TypePiperidine Compound 326 (65 mg, 0.1 mmol) and 95% ethanol (3 mL) at atemperature of about 25° C. was added 2N aqueous NaOH (0.1 mL). Theresulting reaction mixture was stirred at about 25° C. for 2 h afterwhich a white precipitate formed. The precipitate was collected anddried under reduced pressure to provide 42.1 mg of the sodium salt ofSubstituted-Quinoxaline-Type Piperidine Compound 327 (yield 71%).

The compound of formula FX was prepared as follows:

To a mixture of diethyl fumarate (8.68 g, 50.4 mmol, Sigma-Aldrich) andtoluene (800 mL) at 105° C. was added dropwise over 1 h a mixture offormaldehyde, in the form of paraformaldehyde, (10.2 g, 339 mmol (basedon formaldehyde monomer molecular weight), Sigma-Aldrich) and2-(benzylamino)acetic acid (12.2 g, 60.5 mmol, Sigma-Aldrich). Theresulting reaction mixture was refluxed for 16 h in an apparatuscomprising a Dean-Stark trap. After concentration under reducedpressure, the residue was dissolved in hexanes, filtered, andconcentrated under reduced pressure to provide a brown oil. Flashchromatography of the oil with a silica gel column eluting with 1:5EtOAc:hexanes provided 13.8 g of the compound of formula FU as acolorless oil (yield 74%).

The identity of the compound of formula FU, (3S,4S)-diethyl1-benzylpyrrolidine-3,4-dicarboxylate, was confirmed using TLC andLC/MS.

Compound FU: TLC (SiO₂) 1:1 EtOAc:hexanes: Rf=0.8 with UV detection,Dragendorffs reagent; LC/MS: m/z=306 [M+H]⁺ (Calc: 305).

Under a hydrogen atmosphere, a mixture of the compound of formula FU(4.08 g, 13.4 mmol), 10% palladium on carbon (4.7 g), and MeOH wasstirred at a temperature of about 25° C. for 2 h. The Pd/C was filteredoff with a CELITE pad and the filtrate was concentrated under reducedpressure to provide 2.89 g of the compound of formula FV as a paleyellow oil (yield >98%).

The identity of the compound of formula FV, (3S,4S)-diethylpyrrolidine-3,4-dicarboxylate, was confirmed using TLC and LC/MS.

Compound FV: TLC (SiO₂) 1:3 EtOAc:hexanes: Rf=0.1 with UV detection,Dragendorffs reagent; LC/MS: m/z=216 [M+H]⁺ (Calc: 215).

To a mixture of the compound of formula FV (2.4 g, 11.2 mmol) and dryDMF (150 mL) at a temperature of about 25° C. was added tert-butyl2-bromoethylcarbamate (2.7 g, 12.3 mmol, Sigma-Aldrich) and TEA (22.4mmol, 3.1 mL). The resulting reaction mixture was heated to 60° C. andstirred for 18 h at that temperature. Thereafter the solids werefiltered off, the filtrate was washed with brine, and the aqueous phasewas extracted three times with with EtOAc (100 mL for each extraction).The organic portions were combined, dried (MgSO₄), and concentratedunder reduced pressure to provide an oil. Flash chromatography of theoil with a silica gel column eluting with 9:1 CH₂Cl₂:MeOH provided 2.59g of the compound of formula FW as a pale yellow oil (yield 65%).

The identity of the compound of formula FW, (3S,4S)-diethyl1-(2-(tert-butoxycarbonylamino)ethyl)pyrrolidine-3,4-dicarboxylate, wasconfirmed using TLC and LC/MS.

Compound FW: TLC (SiO₂) 5:1 EtOAc:hexanes: Rf=0.6 with UV detection,Dragendorffs reagent; LC/MS: m/z=359 [M+H]⁺ (Calc: 358).

To a mixture of the compound of formula FW (1.5 g, 4.2 mmol) and EtOAcat 0° C. was added slowly 4N HCl in EtOAc (4.5 mL). After heating to atemperature of about 25° C. and stirring for 2 h, the reaction mixturebecame cloudy, indicating the formation of an HCl salt. Afterconcentration under reduced pressure, the residue was washed withdiethyl ether and the solids were filtered off and the dried underreduced pressure for 16 h to provide 1.08 g of the compound of formulaFX as a white solid (yield 90%).

The identity of the compound of formula FX was confirmed using LC/MS.

Compound FX: LC/MS: m/z=259 [M+H]⁺ (Calc: 258).

Substituted-Quinoxaline-Type Piperidine Compound 329 was prepared byusing (3R,4S)-diethyl 1-(2-aminoethyl)pyrrolidine-3,4-dicarboxylate (FY)in place of serine amide hydrochloride (yield 86%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 329,(3R,4S)-diethyl1-(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)ethyl)pyrrolidine-3,4-dicarboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 329: ¹H NMR: δ_(H) (400MHz, CD₃OD): 7.49-5.56 (m, 1H), 7.45-7.49 (s, br, 1H), 7.25-7.22 (m,2H), 6.77-6.67 (s, br, 1H), 5.64-4.86 (s, br., 1H), 4.17-4.12 (dd,J=9.1, 8.2 Hz, 4H), 3.72 (s, br, 2H), 3.62-3.58 (dd, J=5.8, 11.5 Hz,2H), 3.32-3.24 (m, 4H), 2.82-2.74 (m, 4H), 2.5-1.25 (m, 23H), 1.15 (t,J=7.1 Hz, 6H); LC/MS: m/z=566 [M+H]⁺ (Calc: 565).

In a manner similar to the above preparation of the compound of formulaFX, the compound of formula FY was prepared except that diethyl maleate(Sigma-Aldrich) was used in place of diethyl fumarate (yield 30% forfour steps).

The identity of the compound of formula FY was confirmed using LC/MS.

Compound FY: LC/MS: m/z=259 [M+H]⁺ (Calc: 258).

5.17 Example 17

In a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 347 from the compound of formula EH in Example 14,Substituted-Quinoxaline-Type Piperidine Compound 403, i.e.,3-chloro-1-((exo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)quinoxalin-2(1H)-oneor the exo isomer, was prepared from the compound of formula EI.

In a manner similar to Example 15, the followingSubstituted-Quinoxaline-Type Piperidine Compound was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 403 (yield 61%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 104,(2S)-2-(4-((exo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)-3-hydroxypropanamide,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 104: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.70 (1H, s), 7.49 (1H, s), 7.38 (1H, t, J=4.82 Hz), 7.19(4H, m), 5.02 (2H, m), 4.47-4.43 (1H, m), 3.68 (4H, m), 2.81 (2H, m),1.58 (21H, m); LC/MS (96%, t_(r)=1.14 min): m/z=468.2 [M+H]⁺ (Calc:467.6).

In a manner similar to the above preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 104, the followingSubstituted-Quinoxaline-Type Piperidine Compound was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 403 except that(R)-3-amino-1,2-propanediol (Sigma-Aldrich) was used in place of serineamide hydrochloride (yield 70%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 105,1-((exo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-((R)-2,3-dihydroxypropylamino)quinoxalin-2(1H)-one,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 105: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 9.38 (0.1H, s), 7.69 (0.9H, s), 7.31 (4H, m), 5.00 (1.5H,d, J=5.07 Hz), 4.71 (1H, t, J=5.58 Hz), 4.28 (0.5H, s), 3.71 (1H, t,J=5.83 Hz), 3.55 (2H, t, J=6.59 Hz), 3.39 (3H, m), 2.80 (2H, br), 1.64(23H, m); LC/MS (100%, t_(r)=1.14 min): m/z=455.2 [M+H]⁺ (Calc: 454.6).

In a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compounds 144 and 106 in Example 16, the followingSubstituted-Quinoxaline-Type Piperidine Compounds were prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 403.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 146,ethyl2-(4-((exo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)acetate,was confirmed using ¹H NMR.

Substituted-Quinoxaline-Type Piperidine Compound 146: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.92 (1H, s), 7.68 (1H, s), 7.36 (1H, dd, J=7.60, 2.03Hz), 7.21 (2H, q, J=7.94 Hz), 4.98 (1H, br), 4.15-4.08 (2H, m), 3.55(2H, s), 2.80 (2H, s), 1.57 (23H, m).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 110,2-(4-((exo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)aceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 110: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.68 (1H, s), 7.53 (1H, t, J=5.32 Hz), 7.40-7.38 (1H, m),7.23-7.17 (2H, m), 5.02 (1H, br), 3.85 (2H, d, J=5.07 Hz), 3.66 (2H, s),2.82 (2H, s), 1.97-1.41 (21H, m); LC/MS (98%, t_(r)=1.38 min): m/z=439.2[M+H]⁺ (Calc: 438.6).

5.18 Example 18

In a manner similar to Example 15, the followingSubstituted-Quinoxaline-Type Piperidine Compounds were prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 347.

Substituted-Quinoxaline-Type Piperidine Compound 147 was prepared byusing L-serine benzyl ester (i.e., (S)-benzyl2-amino-3-hydroxypropanoate hydrochloride, Sigma-Aldrich) in place ofserine amide hydrochloride (yield 93%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 147,(2S)-benzyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)-3-hydroxypropanoate,was confirmed using ¹H NMR.

Substituted-Quinoxaline-Type Piperidine Compound 147: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.39-7.28 (9H, m), 4.68-4.64 (1H, m), 4.49 (2H, d, J=6.08Hz), 4.04-3.87 (2H, m), 3.62 (2H, t, J=5.58 Hz), 2.37 (1H, s), 2.28-2.18(2H, m), 2.03 (4H, d, J=34.47 Hz), 1.79-1.39 (17H, m).

Under a hydrogen atmosphere, a mixture of Substituted-Quinoxaline-TypePiperidine Compound 147 (176 mg, 0.32 mmol), 10% palladium on carbon (20mg), and MeOH (5 mL) was stirred at a temperature of about 25° C. for 3hr. After the Pd/C was filtered off, the mixture was washed with EtOAcand the filtrate was concentrated under reduced pressure. The resultingsolid was chromatographed with a silica gel column eluted with agradient of from 95:5:0.5 CHCl₃:MeOH:aqueous ammonia to 4:1:0.1CHCl₃:MeOH:aqueous ammonia to provide Substituted-Quinoxaline-TypePiperidine Compound 100 as a colorless solid. Acidifying the solid with2N aqueous HCl (2 mL) provided a white precipitate which was collectedby filtration and washed twice with water (3 mL for each wash) toprovide 67 mg of the hydrochloride of Substituted-Quinoxaline-TypePiperidine Compound 100 as a colorless solid (yield 45%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 100,(2S)-2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)-3-hydroxypropanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 100: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 10.48 (1H, s), 7.88 (1H, d, J=7.6 Hz), 7.41 (2H, m), 7.26(2H, m), 5.91 (1H, t, J=9.38 Hz), 4.61-4.57 (1H, m), 4.21 (2H, s), 3.90(2H, m), 2.94 (1H, s), 2.69 (2H, m), 2.40-1.38 (22H, m); LC/MS (98%,t_(r)=1.42 min): m/z=469.2 [M+H]⁺ (Calc: 468.6).

Substituted-Quinoxaline-Type Piperidine Compound 150 was prepared byusing D-serine benzyl ester (i.e., (R)-benzyl2-amino-3-hydroxypropanoate hydrochloride, Sigma-Aldrich) in place ofserine amide hydrochloride (yield 62%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 150,(2R)-benzyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)-3-hydroxypropanoate,was confirmed using MS.

Substituted-Quinoxaline-Type Piperidine Compound 150: MS: m/z=559.3[M+H]⁺ (Calc: 558.3).

In a manner similar to the above preparation of the hydrochloride ofSubstituted-Quinoxaline-Type Piperidine Compound 100 fromSubstituted-Quinoxaline-Type Piperidine Compound 147, the hydrochlorideof Substituted-Quinoxaline-Type Piperidine Compound 115 was preparedfrom Substituted-Quinoxaline-Type Piperidine Compound 150 (yield 93%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 115,(2R)-2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)-3-hydroxypropanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 115: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 10.60 (0.9H, d, J=5.07 Hz), 9.79 (0.1H, s), 7.92 (0.9H,d, J=7.6 Hz), 7.81 (0.1H, d, J=8.11 Hz), 7.49-7.45 (2H, m), 7.28-7.23(2H, m), 6.00-5.91 (0.9H, m), 5.16 (0.1H, s), 4.65-4.62 (1H, m), 4.20(2H, s), 3.94-3.90 (2H, m), 2.94 (1H, s), 2.78-2.61 (2H, m), 2.28 (6H,m), 2.02-1.37 (14H, m); LC/MS (100%, t_(r)=1.39 min): m/z=469.2 [M+H]⁺(Calc: 468.6)

Substituted-Quinoxaline-Type Piperidine Compound 229 was prepared byusing ethyl 2-(2-(benzyloxy)ethylamino)acetate (Sigma-Aldrich) in placeof serine amide hydrochloride (yield 76%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 229,ethyl2-((2-(benzyloxy)ethyl)(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)amino)acetate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 229: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.43 (1H, d, J=8.0 Hz), 7.35-7.20 (6H, m), 7.18 (2H, m),5.20 (1H, m), 4.60 (2H, m), 4.51 (2H, s), 4.14 (1H, q, H=8.0 Hz), 4.06(2H, m), 3.86 (2H, m), 3.63 (2H, m), 2.36 (1H, m), 2.25 (2H, m),2.10-1.90 (4H, m), 1.90-1.40 (16H, m), 1.25 (3H, t, J=8.0 Hz); LC/MS:m/z=601 [M+H]⁺ (Calc: 600.3).

Substituted-Quinoxaline-Type Piperidine Compound 230 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 229 in a manner similarto that described above except that the acid treatment was omitted(yield 48%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 230,ethyl2-((4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)(2-hydroxyethyl)amino)acetate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 230: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.45 (1H, d, J=8.0 Hz), 7.35 (1H, d, J=8.0 Hz), 7.20 (1H,m), 7.15 (1H, m), 5.15 (1H, br), 4.39 (2H, m), 4.25 (2H, q, J=8.0 Hz),4.02 (2H, m), 3.89 (2H, m), 3.64 (2H, m), 2.40-1.30 (23H, m), 1.31 (3H,t, J=8.0 Hz); LC/MS: m/z=511 [M+H]⁺ (Calc: 510.3).

Substituted-Quinoxaline-Type Piperidine Compound 231 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 230 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 62%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 231,2-((4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)(2-hydroxyethyl)amino)aceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 231: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.35 (2H, m), 7.24 (1H, t, J=8.0 Hz), 7.16 (1H, t, J=8.0Hz), 5.20 (1H, br), 4.48 (2H, m), 3.82 (2H, m), 3.72 (2H, m), 3.66 (2H,m), 2.60-1.30 (23H, m); LC/MS (100%, t_(r)=1.47 min): m/z=483 [M+H]⁺(Calc: 482.3).

5.19 Example 19

In a manner similar to Example 17 except that L-serine benzyl esterhydrochloride was used, the following Substituted-Quinoxaline-TypePiperidine Compound was prepared from Substituted-Quinoxaline-TypePiperidine Compound 403 (yield 50%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 151,(2S)-benzyl2-(4-((exo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)-3-hydroxypropanoate,was confirmed using MS.

Substituted-Quinoxaline-Type Piperidine Compound 151: MS: m/z=559.3[M+H]⁺ (Calc: 558.7).

In a manner similar to Example 18 except that the acidification wasomitted, Substituted-Quinoxaline-Type Piperidine Compound 107 wasprepared from the compound of formula 151 (yield 63%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 107,(2S)-2-(4-((exo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)-3-hydroxypropanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 107: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.75 (1H, s), 7.40 (1H, dd, J=7.10, 2.03 Hz), 7.26 (3H,m), 4.99 (1H, s), 4.45 (1H, t, J=3.8 Hz), 3.86 (41-1, m), 2.91 (2H, s),1.79 (21H, m); LC/MS (100%, t_(r)=1.33 min): m/z=469.2 [M+H]⁺ (Calc:468.6).

5.20 Example 20

In a manner similar to Example 15, Substituted-Quinoxaline-TypePiperidine Compound 152 was prepared from Substituted-Quinoxaline-TypePiperidine Compound 347.

Substituted-Quinoxaline-Type Piperidine Compound 152, i.e., tert-butyl(3R)-1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)pyrrolidin-3-ylcarbamate,was prepared by using (R)-tert-butyl pyrrolidin-3-ylcarbamate(Sigma-Aldrich) in place of serine amide hydrochloride. In a mannersimilar to the preparation of Substituted-Quinoxaline-Type PiperidineCompound 5 in Example 7, the free Substituted-Quinoxaline-TypePiperidine Compound 101 was prepared from Substituted-Quinoxaline-TypePiperidine Compound 152. Thereafter, the hydrochloride ofSubstituted-Quinoxaline-Type Piperidine Compound 101 was prepared in amanner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 174 in Example 7 (overall yield 84%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 101,3-((R)-3-aminopyrrolidin-1-yl)-1-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)quinoxalin-2(1H)-one,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 101: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 10.67 (1H, s), 8.40 (3H, s), 7.85 (1H, d, J=9.12 Hz),7.49 (1H, d, J=6.08 Hz), 7.22 (2H, td, J=8.49, 5.24 Hz), 5.89 (1H, t,J=9.38 Hz), 4.22-3.86 (9H, m), 2.92 (1H, s), 2.61 (2H, m), 2.27-1.37(22H, m); LC/MS (98%, t_(r)=0.78 min): m/z=450.2 [M+H]⁺ (Calc: 449.6).

5.21 Example 21

In a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 70 from the compound of formula AB in Example 12,Substituted-Quinoxaline-Type Piperidine Compound 153 was prepared fromdiethyl 2-oxomalonate and the compound of formula EF (yield 40%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 153,ethyl4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR.

Substituted-Quinoxaline-Type Piperidine Compound 153: ¹H NMR: δ_(H) (300MHz, CDCl₃): 7.91 (1H, d, J=8.1 Hz), 7.63-7.55 (2H, m), 7.34 (1H, t,J=7.4 Hz), 5.21 (1H, br s), 4.50 (2H, q, J=7.1 Hz), 3.66 (2H, br s),2.43-2.15 (5H, m), 2.07-1.93 (2H, m), 1.88-1.35 (20H, m).

Substituted-Quinoxaline-Type Piperidine Compound 74 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 153 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 63%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 74,4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 74: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 10.38 (1H, br s), 8.06 (1H, d, J=8.6 Hz), 7.89 (1H, d,J=7.6 Hz), 7.76 (1H, t, J=7.6 Hz), 7.47 (1H, t, J=7.6 Hz), 6.00-5.91(1H, m), 4.24 (2H, br s), 2.99-2.89 (1H, m), 2.67-2.59 (2H, m),2.38-1.38 (20H, m); LC/MS (99%, t_(r)=1.02 min): m/z=410.2 [M+H]⁺ (Calc:409).

At a temperature of about 25° C., a reaction mixture ofSubstituted-Quinoxaline-Type Piperidine Compound 74 (150 mg, 0.37 mmol),6-methoxypyridin-3-amine (0.55 mmol, Sigma-Aldrich), WSCI (0.74 mmol),and HOBT.H₂O (0.74 mmol, Sigma-Aldrich) in DMF (4 mL) was stirred for 4hr. The mixture was quenched with saturated aqueous NaHCO₃, extractedthree times with EtOAc/water (40 mL for each extraction), washed twicewith water (20 mL for each wash), dried (MgSO₄), and concentrated underreduced pressure to provide a yellow solid. The solid was trituratedwith 4:1:0.5 Et₂O:n-hexane:EtOAc (20 mL), sonicated, and filtrated toprovide a yellow solid. The solid was dried under reduced pressure at70° C. for 12 hr to provide 133 mg of Substituted-Quinoxaline-TypePiperidine Compound 120 (yield 70%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 120,4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-N-(6-methoxypyridin-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 120: ¹H NMR: δ_(H)(400MHz, DMSO-d₆): 10.82 (1H, s), 8.47 (1H, d, J=2.53 Hz), 8.02 (1H, dd,J=8.87, 2.79 Hz), 7.92 (1H, d, J=8.11 Hz), 7.77 (1H, d, J=7.1 Hz), 7.65(1H, d, J=8.62 Hz), 7.46 (1H, t, J=7.6 Hz), 6.88 (1H, d, J=8.62 Hz),5.29 (1H, s), 3.85 (3H, s), 3.65 (2H, s), 2.30-1.37 (23H, m); LC/MS(100%, t_(r)=1.73 min): m/z=516.2 [M+H]⁺ (Calc: 515.7).

5.22 Example 22

In a manner similar to Example 21, the followingSubstituted-Quinoxaline-Type Piperidine Compounds (“endo” isomers) wereprepared from Substituted-Quinoxaline-Type Piperidine Compound 74.

Substituted-Quinoxaline-Type Piperidine Compound 121 was prepared byusing O-methylhydroxylamine (Sigma-Aldrich) in place of 4-methoxyaniline(yield 54%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 121,4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-N-hydroxy-3-oxo-3,4-dihydroquinoxaline-2-carboxamide,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 121: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 11.71 (1H, s), 7.89 (1H, d, J=7.6 Hz), 7.77 (1H, s), 7.44(1H, s), 5.26 (0.811, s), 4.23 (0.211, s), 3.74 (3H, s), 3.58 (2H, m),2.39-1.39 (23H, m); LC/MS (98%, t_(r)=1.20 min): m/z=439.2 [M+H]⁺ (Calc:438.6).

Substituted-Quinoxaline-Type Piperidine Compound 125 was prepared byusing 3-amino-1,2-propanediol (Sigma-Aldrich) in place of4-methoxyaniline (yield 16%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 125,4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-N-(2,3-dihydroxypropyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 125: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 10.09 (1H, s), 8.17 (1H, d, J=8.11 Hz), 7.67 (2H, m),7.43 (1H, t, J=7.6 Hz), 5.30 (1H, br), 3.93 (1H, t, J=4.82 Hz), 3.69(6H, m), 2.37-1.22 (25H, m); LC/MS (96%, t_(r)=1.00 min): m/z=483.2[M+H]⁺ (Calc: 482.6).

Substituted-Quinoxaline-Type Piperidine Compound 317 was prepared byusing (2H-tetrazol-5-yl)methanamine hydrochloride (FFC) in place of4-methoxyaniline and DIC in place of WSCI (yield 29%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 317,N-((2H-tetrazol-5-yl)methyl)-4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 317: ¹H NMR: δ_(H) (400MHz, CD₃OD): 8.06 (d, 1H, J=7.9 Hz), 7.83-7.84 (m, 2H), 7.52-7.56 (m,1H) 5.57-5.59 (m, 1H), 5.01 (s, 2H), 4.38 (m, 2H), 3.15 (m, 1H)2.77-2.80 (m, 2H), 1.47-2.54 (m, 20H); LC/MS: m/z=491 [M+H]⁺ (Calc:490).

(2H-tetrazol-5-yl)methanamine hydrochloride (FFC) was prepared asfollows:

A mixture of benzyl cyanomethylcarbamate (FFA, 2.00 g, 10.5 mmol,Sigma-Aldrich), sodium azide (1.37 g, 21.0 mmol), zinc bromide (1.18 g,5.26 mmol, Sigma-Aldrich), 2-propanol (15 mL), and water (30 mL) at atemperature of about 25° C. was stirred for 15 h. To the reactionmixture was added 2N aqueous HCl (7 mL). The mixture was partitionedbetween EtOAc and water, the organic portion was separated, washed withbrine, dried (Na₂SO₄), filtered, and concentrated under reduced pressureto provide 1.51 g of the compound of formula FFB as a white solid (yield61%).

The identity of the compound of formula FFB, benzyl(2H-tetrazol-5-yl)methylcarbamate, was confirmed using LC/MS.

Compound FFB: LC/MS: m/z=234 [M+H]⁺ (Calc: 233).

Under a hydrogen atmosphere, a mixture of the compound of formula FFC(754 mg, 3.23 mmol), 20% palladium on carbon (50 mg), and MeOH (8 mL)was stirred at a temperature of about 25° C. for 1 h. The Pd/C wasfiltered off with a CELITE pad, the mixture was washed with MeOH, thenconcentrated under reduced pressure to provide 438 mg of the compound offormula FFC as a yellow oil (yield >98%).

Substituted-Quinoxaline-Type Piperidine Compound 154 was prepared byusing glycine ethyl ester in place of 4-methoxyaniline (yield 96%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 154,ethyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)acetate,was confirmed using ¹H NMR.

Substituted-Quinoxaline-Type Piperidine Compound 154: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 9.25 (1H, m), 7.90 (1H, t, J=4.06 Hz), 7.76 (1H, t, J=7.1Hz), 7.62 (1H, d, J=8.62 Hz), 7.44 (1H, t, J=7.6 Hz), 5.23 (1H, br),4.13 (4.2H, m), 3.65 (2H, s), 2.37-1.45 (23H, m), 1.23 (3H, t, J=7.1Hz).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound128 was prepared from Substituted-Quinoxaline-Type Piperidine Compound154 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield30%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 128,2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)aceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 128: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 12.78-12.74 (1H, m), 10.33 (0.9H, br), 9.38 (0.1H, s),9.10 (1H, t, J=5.58 Hz), 8.04 (1H, d, J=8.11 Hz), 7.92 (1H, dd, J=7.86,1.27 Hz), 7.76 (1H, t, J=7.35 Hz), 7.47 (1H, t, J=7.6 Hz), 5.93 (0.9H,t, J=9.12 Hz), 5.20 (0.1H, s), 4.25 (2H, s), 4.03 (2H, d, J=5.58 Hz),2.94 (1H, s), 2.61 (2H, m), 2.35-1.37 (20H, m); LC/MS (96%, t_(r)=1.18min): m/z=467.3 [M+H]⁺ (Calc: 466.6).

Substituted-Quinoxaline-Type Piperidine Compound 375 was prepared byusing (S)-(+)-methyl 2-amino-2-phenylacetate hydrochloride in place of4-methoxyaniline (yield 49%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 375,(S)-methyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)-2-phenylacetate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 375: LC/MS: m/z=557[M+H]⁺ (Calc: 556).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound311 was prepared from Substituted-Quinoxaline-Type Piperidine Compound375 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield30%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 311,(S)-2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)-2-phenylaceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 311: ¹H NMR: δ_(H) (400MHz, CD₃OD): 7.69-7.96 (m, 3H), 7.24-7.45 (m, 6H), 5.61 (s, 1H),5.21-5.55 (m, 1H), 4.19-4.27 (m, 2H), 3.03-3.04 (m, 1H), 1.33-2.76 (m,22H); LC/MS: m/z=543 [M+H]⁺ (Calc: 542).

Substituted-Quinoxaline-Type Piperidine Compound 155 was prepared byusing L-serine methyl ester hydrochloride (i.e., (S)-methyl2-amino-3-hydroxypropanoate hydrochloride, Sigma-Aldrich) in place of4-methoxyaniline (yield >98%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 155,(2S)-methyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)-3-hydroxypropanoate,was confirmed using ¹H NMR.

Substituted-Quinoxaline-Type Piperidine Compound 155: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 9.44 (1H, m), 7.92 (1H, d, J=8.11 Hz), 7.77 (1H, t,J=7.35 Hz), 7.62 (1H, d, J=8.62 Hz), 7.45 (1H, t, J=7.6 Hz), 5.22 (1H,br), 5.21 (1H, t, J=5.58 Hz), 4.61-4.56 (1H, m), 3.86-3.81 (1H, m), 3.70(6H, m), 1.89 (23H, m).

Substituted-Quinoxaline-Type Piperidine Compound 129 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 155 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 78%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 129,(2S)-2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)-3-hydroxypropanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 129: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 9.30 (1H, s), 7.92 (1H, dd, J=7.86, 1.27 Hz), 7.72 (2H,m), 7.44 (1H, t, J=7.86 Hz), 5.36 (1H, br), 4.44-4.40 (1.1H, m), 3.77(4H, m), 2.34 (2H, m), 2.08 (4H, m), 1.91-1.40 (17H, m); LC/MS (98%,t_(r)=1.15 min): m/z=497.2 [M+H]⁺ (Calc: 496.6).

Substituted-Quinoxaline-Type Piperidine Compound 376 was prepared byusing methyl pyrrolidine-2-carboxylate hydrochloride (Bachem Americas,Inc., Torrance, Calif.) in place of 4-methoxyaniline and DIC in place ofWSCI (yield 29%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 376,methyl1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carbonyl)pyrrolidine-2-carboxylate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 376: LC/MS: m/z=521[M+H]⁺ (Calc: 520).

Substituted-Quinoxaline-Type Piperidine Compound 306 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 376 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 40%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 306,1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carbonyl)pyrrolidine-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 306: ¹H NMR: δ_(H) (400MHz, CD₃OD): 7.39-7.90 (m, 4H), 5.28-5.50 (m, 1H), 4.35-4.42 (m, 1H),3.54-3.79 (m, 5H), 1.45-2.35 (m, 24H); LC/MS: m/z=507 [M+H]⁺ (Calc:506).

Substituted-Quinoxaline-Type Piperidine Compound 377 was prepared byusing ethyl piperidine-4-carboxylate (Sigma-Aldrich) in place of4-methoxyaniline and DIC in place of WSCI (yield 29%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound anethyl1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carbonyl)piperidine-4-carboxylate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 377: LC/MS: m/z=549[M+H]⁺ (Calc: 548).

Substituted-Quinoxaline-Type Piperidine Compound 316 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 377 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 23%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 316,1-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carbonyl)piperidine-4-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 316: ¹H NMR: δ_(H) (400MHz, CD₃OD): 7.91 (dd, 1H, J=1.2 Hz, 7.9 Hz), 7.79-7.87 (m, 1H),7.75-7.77 (m, 1H), 7.48-7.51 (m, 1H), 5.59-5.63 (m, 08H), 5.30 (m,0.2H), 4.52 (m, 1H), 4.49 (m, 2H), 3.67-3.70 (m, 1H), 3.14-3.32 (m, 3H),1.46-2.84 (m, 27H); LC/MS: m/z=521 [M+H]⁺ (Calc: 520).

Substituted-Quinoxaline-Type Piperidine Compound 378 was prepared byusing methyl 6-(aminomethyl)nicotinate hydrochloride (FFF) in place of4-methoxyaniline and DIC in place of WSCI (yield 39%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 378,methyl6-((4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)methyl)nicotinate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 378: LC/MS: m/z=558[M+H]⁺ (Calc: 557).

Substituted-Quinoxaline-Type Piperidine Compound 318 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 378 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 32%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 318,6-((4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)methyl)nicotinicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 318: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 9.43-9.46 (m, 1H), 9.03 (d, 1H, J=1.1 Hz), 8.27 (dd, 1H,J=1.9 Hz, 8.1 Hz), 7.89 (d, 1H, J=7.7 Hz), 7.67-7.75 (m, 2H), 7.59 (d,1H, J=8.1 Hz), 7.42-7.46 (m, 1H), 5.21-5.42 (m, 1H), 4.65 (d, 2H, J=5.7Hz), 3.65-3.76 (m, 2H), 1.42-2.35 (m, 23H); LC/MS: m/z=544 [M+H]⁺ (Calc:543).

Methyl 6-(aminomethyl)nicotinate hydrochloride (FFF) was prepared asfollows:

To a mixture of 6-cyanonicotinic acid (FFD, 1.00 g, 6.75 mmol,Sigma-Aldrich) and DMF (4 drops) in CHCl₃ (20 mL) at a temperature ofabout 25° C. was added thionyl chloride (1.08 mL, 14.85 mmol). Thereaction mixture was refluxed for 2 h, then concentrated under reducedpressure to provide a residue. The residue was dissolved in MeOH (20mL), stirred at a temperature of about 25° C. for 2 h, then concentratedunder reduced pressure to provide 1.34 g of the compound of formula FFE,methyl 6-cyanonicotinate hydrochloride, as a pale yellow solid(yield >98%). Under a hydrogen atmosphere, a mixture of the compound offormula FFE (1.34 g, 6.75 mmol), 20% palladium on carbon (650 mg), andMeOH (20 mL) was stirred at a temperature of about 25° C. for 16 h. ThePd/C was filtered off with a CELITE pad, the mixture was washed withMeOH, then recrystalized from EtOAc/MeOH/hexane to provide 488.2 mg ofthe compound of formula FFF as a purple solid (yield 36%).

Substituted-Quinoxaline-Type Piperidine Compound 379 was prepared byusing ethyl 3-aminopropanoate hydrochloride (Sigma-Aldrich) in place of4-methoxyaniline and DIC in place of WSCI (yield 73%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 379,ethyl3-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)propanoate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 379: LC/MS: m/z=509[M+H]⁺ (Calc: 508).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound350 was prepared from Substituted-Quinoxaline-Type Piperidine Compound379 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield34%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 350,3-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)propanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 350: ¹H NMR: δ_(H) (400MHz, CD₃OD): 7.92-7.94 (m, 1H), 7.67-7.74 (m, 2H), 7.38-7.42 (m, 1H),5.50 (m, 1H), 4.25 (m, 2H), 3.63 (t, 2H, J=6.5 Hz), 3.02-3.04 (m, 1H),2.63-2.68 (m, 2H), 2.59 (t, 2H, J=6.5 Hz), 2.28-2.57 (m, 6H), 1.35-1.86(14H, m); LC/MS: m/z=481 [M+H]⁺ (Calc: 480).

Substituted-Quinoxaline-Type Piperidine Compound 380 was prepared byusing methyl 2-amino-3-(1H-imidazol-4-yl)propanoate hydrochloride(Sigma-Aldrich) in place of 4-methoxyaniline and DIC in place of WSCI(yield 29%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 380,methyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)-3-(1H-imidazol-4-yl)propanoate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 380: LC/MS: m/z=561[M+H]⁺ (Calc: 560).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound351 was prepared from Substituted-Quinoxaline-Type Piperidine Compound380 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield34%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 351,2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)-3-(1H-imidazol-4-yl)propanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 351: ¹H NMR: δ_(H) (400MHz, CD₃OD): 8.87 (s, 1H), 8.02 (m, 2H), 7.80-7.84 (m, 1H), 7.52 (m,1H), 7.47 (s, 1H), 5.80 (m, 1H), 5.09 (m, 1H), 4.36 (m, 2H), 3.52-3.55(m, 1H), 3.13 (m, 1H), 1.45-2.80 (m, 21H); LC/MS: m/z=547 [M+H]⁺ (Calc:546).

Substituted-Quinoxaline-Type Piperidine Compound 381 was prepared byusing methyl 2-amino-3-phenylpropanoate hydrochloride (Sigma-Aldrich) inplace of 4-methoxyaniline and DIC in place of WSCI (yield 53%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 381,methyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)-3-phenylpropanoate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 381: LC/MS: m/z=571[M+H]⁺ (Calc: 570).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound352 was prepared from Substituted-Quinoxaline-Type Piperidine Compound381 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield15%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 352,2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)-3-phenylpropanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 352: ¹H NMR: δ_(H) (400MHz, CD₃OD): 7.95-7.97 (m, 2H), 7.67-7.73 (m, 2H), 7.40-7.43 (m, 1H),7.14-7.24 (m, 5H), 5.45 (m, 1H), 4.85-4.91 (m, 1H), 4.08-4.27 (m, 2H),3.02-3.04 (m, 1H), 1.35-2.70 (22H, m); LC/MS: m/z=556 [M+H]⁺ (Calc:557).

Substituted-Quinoxaline-Type Piperidine Compound 382 was prepared byusing ethyl 2-(methylamino)acetate hydrochloride (Sigma-Aldrich) inplace of 4-methoxyaniline and DIC in place of WSCI (yield 74%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 382,ethyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-N-methyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)acetate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 382: LC/MS: m/z=509[M+H]⁺ (Calc: 508).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound307 was prepared from Substituted-Quinoxaline-Type Piperidine Compound382 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield23%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 307,2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-N-methyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)aceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 307: ¹H NMR: δ_(H) (400MHz, CD₃OD): 7.78-7.96 (m, 3H), 7.46-7.52 (m, 1H), 5.29-5.64 (m, 1H),4.18-7.90 (m, 4H), 3.11 (s, 3H), 1.46-2.88 (m, 21H); LC/MS: m/z=481[M+H]⁺ (Calc: 480).

Substituted-Quinoxaline-Type Piperidine Compound 383 was prepared byusing methyl 2-amino-2-methylpropanoate hydrochloride (Sigma-Aldrich) inplace of 4-methoxyaniline and DIC in place of WSCI (yield 49%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 383,methyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)-2-methylpropanoate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 383: LC/MS: m/z=509[M+H]⁺ (Calc: 508).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound308 was prepared from Substituted-Quinoxaline-Type Piperidine Compound383 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield16%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 308,2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)-2-methylpropanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 308: ¹H NMR: δ_(H) (400MHz, CD₃OD): 8.06-8.13 (m, 1H), 7.81-7.95 (m, 2H), 7.51-7.55 (m, 1H),5.33-5.66 (m, 1H), 4.38 (m, 2H), 3.14-3.16 (m, 1H), 1.55-2.83 (m, 22H);LC/MS: m/z=495 [M+H]⁺ (Calc: 494).

Substituted-Quinoxaline-Type Piperidine Compound 384 was prepared byusing methyl 2-amino-4-(methylthio)butanoate hydrochloride(Sigma-Aldrich) in place of 4-methoxyaniline and DIC in place of WSCI(yield 44%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 384,methyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)-4-(methylthio)butanoate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 384: LC/MS: m/z=555[M+H]⁺ (Calc: 554).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound309 was prepared from Substituted-Quinoxaline-Type Piperidine Compound384 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield9%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 309,2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)-4-(methylthio)butanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 309: ¹H NMR: δ_(H) (400MHz, CD₃OD): 7.71-7.96 (m, 3H), 7.43 (m, 1H), 5.21-5.50 (m, 1H),4.20-4.27 (m, 2H), 3.03-3.04 (m, 1H), 1.53-2.66 (m, 27H); LC/MS: m/z=541[M+H]⁺ (Calc: 540).

Substituted-Quinoxaline-Type Piperidine Compound 385 was prepared byusing di-tert-butyl 2-aminosuccinate hydrochloride (Bachem Americas,Inc.) in place of 4-methoxyaniline and DIC in place of WSCI (yield 47%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 385,di-tert-butyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)succinate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 385: LC/MS: m/z=637[M+H]⁺ (Calc: 636).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound310 was prepared from Substituted-Quinoxaline-Type Piperidine Compound385 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield14%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 310,2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)succinicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 310: ¹H NMR: δ_(H) (400MHz, CD₃OD): 8.08 (d, 1H, J=7.9 Hz), 7.82-7.98 (m, 2H), 7.52-7.55 (m,1H), 5.51-5.64 (m, 0.8H), 5.32 (m, 0.2H), 5.05 (t, 1H, J=4.8 Hz),4.30-4.38 (m, 2H), 2.98-3.16 (m, 3H), 1.46-2.83 (m, 22H); LC/MS: m/z=525[M+H]⁺ (Calc: 524).

Substituted-Quinoxaline-Type Piperidine Compound 386 was prepared byusing methyl 2-aminopropanoate hydrochloride (Sigma-Aldrich) in place of4-methoxyaniline and DIC in place of WSCI (yield 38%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 386,methyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)propanoate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 386: LC/MS: m/z=495[M+H]⁺ (Calc: 494).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound312 was prepared from Substituted-Quinoxaline-Type Piperidine Compound386 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield14%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 312,2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)propanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 312: ¹H NMR: δ_(H) (400MHz, CD₃OD): 8.08-8.10 (m, 1H), 7.78-7.98 (m, 2H), 7.53-7.56 (m, 1H),5.31-5.53 (m, 1H), 4.71-4.74 (m, 1H), 4.13-4.39 (m, 2H), 3.14-3.23 (m,1H), 1.31-2.81 (m, 25H); LC/MS: m/z=481 [M+H]⁺ (Calc: 480).

Substituted-Quinoxaline-Type Piperidine Compound 387 was prepared byusing methyl 2-amino-4-methylpentanoate hydrochloride (Sigma-Aldrich) inplace of 4-methoxyaniline and DIC in place of WSCI (yield 90%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 387,methyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)-4-methylpentanoate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 387: LC/MS: m/z=537[M+H]⁺ (Calc: 536).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound313 was prepared from Substituted-Quinoxaline-Type Piperidine Compound387 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield9%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 313,2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)-4-methylpentanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 313: ¹H NMR: δ_(H) (400MHz, CD₃OD): 7.69-8.08 (m, 3H), 7.40-7.43 (m, 1H), 5.21-5.53 (m, 1H),4.64-4.67 (m, 1H), 4.20-4.27 (m, 2H), 3.03-3.04 (m, 1H), 1.34-2.71 (m,25H), 0.92 (d, 6H, J=5.8 Hz); LC/MS: m/z=523 [M+H]⁺ (Calc: 522).

Substituted-Quinoxaline-Type Piperidine Compound 388 was prepared byusing methyl 4-(aminomethyl)benzoate hydrochloride (Sigma-Aldrich) inplace of 4-methoxyaniline and DIC in place of WSCI (yield 47%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 388,methyl4-((4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)methyl)benzoate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 388: LC/MS: m/z=557[M+H]⁺ (Calc: 556).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound314 was prepared from Substituted-Quinoxaline-Type Piperidine Compound388 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield73%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 314,4#4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)methyl)benzoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 314: ¹H NMR: δ_(H) (400MHz, CD₃OD): 8.02-8.06 (m, 3H), 7.79-7.89 (m, 2H), 7.50-7.58 (m, 3H),5.63-5.67 (m, 0.8H), 5.32 (m, 0.2H), 4.77 (s, 2H), 4.36 (m, 2H),3.14-3.16 (m, 1H), 1.30-2.82 (m, 22H); LC/MS: m/z=543 [M+H]⁺ (Calc:542).

Substituted-Quinoxaline-Type Piperidine Compound 156 was prepared byusing L-serine benzyl ester in place of 4-methoxyaniline and DIC inplace of WSCI (yield 95%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 156,(2S)-benzyl2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)-3-hydroxypropanoate,was confirmed using ¹H NMR.

Substituted-Quinoxaline-Type Piperidine Compound 156: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 9.47 (1H, m), 7.90 (1H, m), 7.66 (1H, m), 7.61 (1H, m),7.47-7.33 (8H, m), 5.26 (2H, t, J=4.2 Hz), 5.20 (2H, s), 3.89-3.64 (5H,s), 2.44-1.43 (22H, m).

Substituted-Quinoxaline-Type Piperidine Compound 126 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 156 in a manner similarto the final step of Example 18 except that the acidification wasomitted (yield 84%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 126,(2S)-2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-2-carboxamido)-3-hydroxypropanoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 126: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.94 (1H, t, J=8.36 Hz), 7.02 (1H, t, J=7.6 Hz), 6.84(2H, t, J=6.34 Hz), 6.72 (1H, td, J=8.36, 3.72 Hz), 6.50 (1H, d, J=15.21Hz), 4.83 (1H, s), 4.44 (1H, dd, J=6.84, 1.77 Hz), 4.08 (1H, dq,J=16.22, 4.06 Hz), 3.92 (2H, s), 3.69-3.61 (1H, m), 3.47 (1H, m), 2.71(1H, s), 2.42 (1H, m), 2.18-1.39 (22H, m); LC/MS (100%, t_(r)=1.27 min):m/z=499.2 [M+H]⁺ (Calc: 498.6).

5.23 Example 23

Thionyl chloride (214 μL, 0.293 mmol) was added to a mixture ofSubstituted-Quinoxaline-Type Piperidine Compound 74 (120 mg, 293 mmol),a catalytic amount of DMF (5 drops), and CHCl₃ (2 mL) at a temperatureof about 25° C. The reaction mixture was refluxed for 2 h thenconcentrated under reduced pressure to provide a residue. Ethyl2-(2-aminothiazol-4-yl)acetate (71.0 mg, 0.381 mmol, Sigma-Aldrich) wasadded to a mixture of the residue and CHCl₃ (2 mL). The reaction mixturewas stirred at a temperature of about 25° C. for 21 h, 100 μL of TEA wasadded, and the reaction mixture was stirred at a temperature of about25° C. for 24 h more. The mixture was partitioned between DCM and water.The organic portion was separated, washed with brine, dried (MgSO₄),filtered, and concentrated under reduced pressure to provide a residue.The residue was then chromatographed by preparative TLC (eluted with10%:90% MeOH:DCM) to provide 84.5 mg of Substituted-Quinoxaline-TypePiperidine Compound 232 as a pale yellow solid (yield 49.9%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 232,ethyl24244-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)thiazol-4-yl)acetate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 232: LC/MS: m/z=578[M+H]⁺ (Calc: 577).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound233 was prepared from Substituted-Quinoxaline-Type Piperidine Compound232 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield37%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 233,2-(2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)thiazol-4-yl)aceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 233: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 12.64-12.87 (1H, br), 12.44 (1H, br), 10.43 (1H, br),8.13 (1H, m), 7.97 (1H, dd, J=1.0, 7.9 Hz), 7.80-7.84 (1H, m), 7.50-7.53(1H, m), 7.13 (1H, s), 6.02 (1H, m), 4.26 (2H, m), 3.66 (2H, s), 2.94(2H, m), 2.60-2.67 (2H, m), 1.39-2.41 (20H, m); LC/MS: m/z=550 [M+H]⁺(Calc: 549).

5.24 Example 24

In a manner similar to Example 21, the followingSubstituted-Quinoxaline-Type Piperidine Compounds (“exo” isomers) wereprepared from the compound of formula EG.

Substituted-Quinoxaline-Type Piperidine Compound 123 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 158(4-((exo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid) (yield 82%), which was prepared from Substituted-Quinoxaline-TypePiperidine Compound 157 (ethyl4-((exo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate),which was prepared from the compound of formula EG.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 123,4-((exo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-N-(6-methoxypyridin-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 123: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 10.84 (1H, s), 8.45 (1H, d, J=2.53 Hz), 7.98 (3H, dt,J=21.46, 8.24 Hz), 7.76 (1H, s), 7.50 (1H, d, J=7.6 Hz), 6.89 (1H, d,J=9.12 Hz), 5.15 (1H, br), 4.29 (2H, br), 3.85 (3H, s), 2.85 (2H, br),2.33-1.48 (21H, m); LC/MS (99%, t_(r)=1.63 min): m/z=516.3 [M+H]⁺ (Calc:515.7).

5.25 Example 25

To a mixture of sodium iodide (1.29 mmol, Sigma-Aldrich) in acetonitrile(7 mL) was added TMSCl (1.29 mmol, Sigma-Aldrich) and the mixture wasstirred at a temperature of about 25° C. for 30 min. Thereafter, to themixture was added Substituted-Quinoxaline-Type Piperidine Compound 120(133 mg, 0.26 mmol) in acetonitrile (3 mL). The resulting reactionmixture was heated with stirring at 80° C. for 2.5 h. After cooling to atemperature of about 25° C., the reaction mixture was extracted threetimes with EtOAc/water (30 mL for each extraction). The organic portionswere combined, washed with saturated aqueous Na₂SO₃ solution (10 mL),brine (10 mL), dried (MgSO₄), and concentrated under reduced pressure toprovide a yellow solid. The solid was chromatographed with a silica gelcolumn eluted with a gradient of from 97%:3% CHCl₃:MeOH to 85%:15%CHCl₃:MeOH to provide 38 mg of Substituted-Quinoxaline-Type PiperidineCompound 122 as a yellow solid (yield 30%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 122,4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-N-(6-oxo-1,6-dihydropyridin-3-yl)-3,4-dihydroquinoxaline-2-carboxamide,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 122: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 11.44 (0.9H, s), 10.59 (1H, s), 9.73 (0.1H, s), 8.02-7.46(6H, m), 6.41 (1H, d, J=9.63 Hz), 5.50 (1H, br), 4.27 (0.5H, s), 3.65(1.5H, s), 2.36-1.45 (23H, m); LC/MS (98%, t_(r)=1.18 min): m/z=502.2[M+H]⁺ (Calc: 501.6).

In a manner similar to the above preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 122,Substituted-Quinoxaline-Type Piperidine Compound 124 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 123 (yield 53%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 124,4-((exo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-N-(6-oxo-1,6-dihydropyridin-3-yl)-3,4-dihydroquinoxaline-2-carboxamide,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 124: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 11.45 (1H, s), 10.61 (1H, s), 7.96 (3H, m), 7.75 (1H, s),7.50 (2H, m), 6.42 (1H, d, J=9.63 Hz), 5.13 (1H, br), 4.27 (0.5H, br),3.59 (1.5H, br), 2.72 (2H, m), 2.00-1.47 (21H, m); LC/MS (96%,t_(r)=1.02 min): m/z=502.2 [M+H]⁺ (Calc: 501.6).

5.26 Example 26

To a mixture of Substituted-Quinoxaline-Type Piperidine Compound 74 (100mg, 0.23 mmol) in ethanol (3 mL) was added dropwise at a temperature ofabout 25° C. a 50% aqueous solution of hydroxylamine (1 mL,Sigma-Aldrich). The resulting reaction mixture was stirred at atemperature of about 25° C. for 4 h. A yellow precipitate formed.Diethyl ether (20 mL) was added to the precipitate which was thencollected by filtration, washed twice with diethyl ether (5 mL for eachwash), and dried under reduced pressure a temperature of about 25° C.for 12 hr to provide 49 mg of Substituted-Quinoxaline-Type PiperidineCompound 127 as a pale yellow solid (yield 51%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 127,4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-N-hydroxy-3-oxo-3,4-dihydroquinoxaline-2-carboxamide,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 127: ¹H NMR: δ_(H)(400MHz, CD₃OD): 8.02 (1H, d, J=8.11 Hz), 7.78 (2H, t, J=6.59 Hz), 7.51-7.47(1H, m), 5.44 (1H, s), 4.13 (2H, s), 2.95 (1H, s), 2.66-2.58 (2H, m),2.33 (6H, m), 2.02-1.47 (15H, m); LC/MS (100%, t_(r)=1.05 min):m/z=425.2 [M+H]⁺ (Calc: 424.5).

5.27 Example 27

In a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 120 from Substituted-Quinoxaline-Type PiperidineCompound 74 in Example 21, Substituted-Quinoxaline-Type PiperidineCompound 72 was prepared from Substituted-Quinoxaline-Type PiperidineCompound 71 (yield 70%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 72,tert-butyl5-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxaline-2-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 72: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.93 (1H, d, J=8 Hz), 7.84 (1H, d, J=8 Hz), 7.68 (1H, t,J=8 Hz), 7.42 (1H, t, J=8 Hz), 4.75 (1H, br), 3.69 (1H, s), 3.55-2.42(16H, m), 1.71-1.40 (16H, m), 1.39 (9H, s); LC/MS: m/z=578.2 [M+H]⁺(Calc: 577.8).

Substituted-Quinoxaline-Type Piperidine Compound 73 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 72 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound 5in Example 7 (yield 72%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 73,1-(1-cyclooctylpiperidin-4-yl)-3-(octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)quinoxalin-2(1H)-one,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 73: ¹H NMR: δ_(H) (400MHz, DMSO): 7.93 (1H, d, J=8 Hz), 7.83 (1H, d, J=4 Hz), 7.68 (1H, t, J=4Hz), 7.42 (1H, t, J=8 Hz), 4.72 (1H, br), 3.70 (1H, m), 3.48 (1H, m),3.38 (1H, m), 3.09 (1H, m), 2.92-2.38 (13H, m), 1.73-1.43 (17H, m);LC/MS: m/z=478.1 [M+H]⁺ (Calc: 477.6).

5.28 Example 28

To a mixture of cyclooctanone (GA, 17 g, 135 mmol, Sigma-Aldrich) inethanol (200 mL) and water (200 mL) were added KCN (17.5 g, 269 mmol,Sigma-Aldrich) followed by ammonium carbonate ([NH₄]₂CO₃, 51.8 g, 539mmol, Sigma-Aldrich). The resulting reaction mixture was stirred at 80°C. for 6 h. The reaction mixture was evaporated to dryness under reducedpressure to provide a white solid precipitate which was filtered,collected, and dried for 16 h to provide 15.9 g of the compound offormula GB, 1,3-diazaspiro[4.7]dodecane-2,4-dione (yield 73%).

A mixture of the compound of formula GB (15.9 g, 81 mmol) in 2N NaOH wasrefluxed for 96 hr. The reaction mixture was neutralized by the additionof 2N HCl to provide a white solid precipitate which was filtered andcollected to provide the compound of formula GC,1-aminocyclooctanecarboxylic acid. The compound of formula GC wasdissolved with hot phenylmethanol (i.e., phenylmethanol) thenconcentrated HCl was added. The resulting reaction mixture was refluxedfor 16 hr. After neutralizing the reaction mixture with 2N NaOH, theresulting mixture was extracted three times with 4:1 CHCl₃:MeOH. Theorganic portions were combined, washed with water, washed with brine,dried (MgSO₄), filtered, and concentrated under reduced pressure toprovide 920 mg of the compound of formula GD, benzyl1-aminocyclooctanecarboxylate (yield 6% for two steps).

The compound of formula GF was prepared in a manner similar to thepreparation of the compound of formula DB in Example 13 except1-benzylpiperidin-4-one (GE, Sigma-Aldrich) was used in place oftropinone and methyl iodide was used in place of dimethyl sulfate.

At a temperature of 90° C., a mixture of the compound of formula GF (10mmol), MeOH (6 mL) and water (20 mL) was added dropwise to a mixture ofthe compound of formula GD (10 mmol), K₂CO₃ (1 mmol), MeOH (10 mL) andwater (4 mL) over 20 min. The resulting reaction mixture was stirred at90° C. for 48 hr. After concentration under reduced pressure, themixture was extracted three times with a mixture of EtOAc and water. Theorganic portions were combined, dried (MgSO₄), and concentrated underreduced pressure to provide a yellow oil. The resulting oil waschromatographed with a silica gel column eluted with a gradient of from10%:90% EtOAc:n-hexane to 50%:50% EtOAc:n-hexane to provide the compoundof formula GG, benzyl 1-(4-oxopiperidin-1-yl)cyclooctanecarboxylate.

Sodium triacetoxyborohydride (50 mmol) was added to a mixture of thecompound of formula GG (12.8 mmol), and 1,2-phenylenediamine (3 g, 27.8mmol) in 100 mL of CH₂Cl₂ at a temperature of about 25° C. Thereafter, 3mL of acetic acid was added. The resulting mixture was stirred at atemperature of about 25° C. for about 16 h. MeOH (2 mL) and water (25mL) were added and the mixture was neutralized with 28% aqueous ammoniato adjust the pH to about 8. The organic portion was separated, washedwith brine (10 mL), concentrated under reduced pressure, andchromatographed with a silica gel column eluted with 10:1:1EtOAc:MeOH:TEA to provide the compound of formula GH, benzyl1-(4-(2-aminophenylamino)piperidin-1-yl)cyclooctanecarboxylate.

A mixture of the compound of formula GH in 20 mL of diethyl oxalate(Sigma-Aldrich) was heated at 140° C. for 16 h. After cooling to atemperature of about 25° C., the reaction mixture was diluted withEtOAc, washed with 2N aqueous NaOH (30 mL), washed with brine (20 mL),concentrated under reduced pressure, and chromatographed with a silicagel column eluted with 5:5:0.5:0.5 EtOAc:hexane:MeOH:TEA to provide thecompound of formula GI.

The identity of the compound of formula GI, benzyl1-(4-(2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)cyclooctanecarboxylate,was confirmed using ¹H NMR and LC/MS.

Compound GI: ¹H NMR: δ_(H) (300 MHz, DMSO-d₆): 11.51 (1H, s), 7.47 (1H,d, J=8.1 Hz), 7.41-7.33 (5H, m), 7.24-7.17 (3H, m), 5.17 (2H, s), 4.58(1H, br), 3.24 (2H, d, J=11.1 Hz), 2.76 (2H, d, J=9.3 Hz), 2.33 (2H, t,J=10.8 Hz), 2.01-1.47 (16H, m); LC/MS (100%, t_(r)=1.87 min): m/z=490.2[M+H]⁺ (Calc: 489.3).

Alternatively, the compound of formula GD was prepared by the followingroute.

To a mixture of the hydrochloride of the compound of formula GC (414 mg,2.00 mmol), aqueous 1N NaOH (4 mL, 4.00 mmol), and dioxane (4 mL) at atemperature of about 25° C. was added (BOC)₂O (0.51 mL, 2.2 mmol). Afterthe addition, the reaction mixture was stirred for 18 h at a temperatureof about 25° C. The mixture was quenched by pouring it into aqueous 1NHCl and extracted with CHCl₃. The organic portion was dried (Na₂SO₄) andconcentrated under reduced pressure to provide a white solid. The solidwas triturated with iso-propyl ether and collected to provide 221 mg ofthe compound of formula GJ as a colorless solid (yield 41%).

The identity of the compound of formula GJ,1-(tert-butoxycarbonylamino)cyclooctanecarboxylic acid, was confirmedusing ¹H NMR.

Compound GJ: ¹H NMR: δ_(H) (400 MHz, DMSO-d₆): 12.01 (1H, s), 6.90 (1H,s), 1.89-1.45 (14H, m), 1.35 (9H, s).

To a mixture of the compound of formula GJ (215 mg, 0.792 mmol) in DMF(1 mL) at a temperature of about 25° C. was added the compound offormula EB (0.103 mmol, 0.871 mmol) and DIEA (0.166 mL, 0.950 mmol).After the addition, the reaction mixture was stirred for 20 h at atemperature of about 25° C. The mixture was quenched by pouring it intowater. A white precipitate formed. The precipitate was collected, washedwith dilute aqueous NaHCO₃, and washed with water to provide 240 mg ofthe compound of formula GK as a white solid (yield 84%).

The identity of the compound of formula GK, benzyl1-(tert-butoxycarbonylamino)cyclooctanecarboxylate, was confirmed using¹H NMR.

Compound GK: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.37-7.34 (5H, m), 5.16(2H, s), 4.69 (1H, s), 2.08-2.04 (4H, m), 1.57 (10H, d, J=8.06 Hz), 1.43(9H, s).

The compound of formula GD was prepared from the compound of formula GKin a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 5 in Example 7 (yield >98%).

The identity of the compound of formula GD was confirmed using ¹H NMR.

Compound GD: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.40-7.34 (5H, m), 5.21(2H, s), 2.06-1.71 (14H, m).

Alternatively, the compound of formula GI was prepared by the followingroute.

The compound of formula GG was prepared from the compounds of formula GDand GF in a manner similar to that described above (yield 38%).

The identity of the compound of formula GG was confirmed using ¹H NMR.

Compound GG: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.38-7.36 (5H, m), 5.14(2H, s), 2.92 (4H, t, J=5.62 Hz), 2.39 (4H, t, J=5.79 Hz), 2.00-1.59(14H, m).

The compound of formula GL was prepared from the compound of formula GGin a manner similar to the preparation of the compound of formula AB inExample 1 except tert-butyl 2-aminophenylcarbamate (Sigma-Aldrich) wasused in place of 1,2-phenylenediamine (yield 95%).

The identity of the compound of formula GL, benzyl1-(4-(2-(tert-butoxycarbonylamino)phenylamino)piperidin-1-yl)cyclooctanecarboxylate,was confirmed using ¹H NMR.

Compound GL: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.46-7.37 (5H, m), 7.07(2H, dd, J=12.51, 6.13 Hz), 6.78-6.71 (2H, m), 6.10 (1H, s), 5.16 (3H,s), 3.58 (1H, dd, J=9.65, 4.95 Hz), 3.19-2.90 (4H, m), 2.41-1.34 (18H,m), 2.41 (9H, s).

The compound of formula GM was prepared from the compound of formula GLand methyl 2-chloro-2-oxoacetate in a manner similar to the preparationof the compound of formula CF in Example 6 (yield >98%).

The identity of the compound of formula GM, benzyl1-(4-(N-(2-(tert-butoxycarbonylamino)phenyl)-2-methoxy-2-oxoacetamido)piperidin-1-yl)cyclooctanecarboxylate,was confirmed using ¹H NMR.

Compound GM: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 7.98 (1H, d, J=5.1 Hz),7.42-7.32 (5H, m), 7.06-7.04 (2H, m), 6.68 (1H, s), 5.10 (2H, s), 4.35(1H, m), 3.49 (3H, s), 3.02 (2H, t, J=10.8 Hz), 2.90 (1H, t, J=6.0 Hz),2.35 (1H, t, J=6.0 Hz), 2.24 (2H, t, J=12.0 Hz), 1.87-1.78 (6H, m),1.51-1.27 (19H, m).

To the compound of formula GM (553 mg, 0.89 mmol) was added 4N HCl inEtOAc (5.5 mL) at 0° C. Thereafter, the reaction mixture was stirred for30 min at a temperature of about 25° C. A white precipitate formed.Saturated aqueous NaHCO₃ (pH>8) was added and the reaction mixture wasstirred for 30 min at a temperature of about 25° C. Thereafter, themixture was extracted twice with CHCl₃ (50 mL for each extraction). Theorganic portions were combined, washed with water, dried (MgSO₄), andconcentrated under reduced pressure to provide a colorless amorphoussolid. The solid was recrystallized from a mixture of diethyl ether andiso-propyl ether to provide 333 mg of the compound of formula GI as awhite powder (yield 76%).

5.29 Example 29

In a manner similar to Example 3, the compound of formula GN wasprepared from the compound of formula GI (yield 92%) thenSubstituted-Quinoxaline-Type Piperidine Compound 166 was prepared fromtert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and thecompound of formula GN (yield >98%).

The identity of the compound of formula GN, benzyl1-(4-(3-chloro-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)cyclooctanecarboxylate,was confirmed using ¹H NMR.

Compound GN: ¹H NMR: δ_(H) (300 MHz, CDCl₃): 7.81 (1H, d, J=8.1 Hz),7.59-7.56 (2H, m), 7.39-7.35 (6H, m), 5.16 (2H, s), 4.83 (1H, br), 3.49(3H, s), 3.25 (2H, d, J=11.7 Hz), 2.91 (2H, m), 2.34 (2H, t, J=6.0 Hz),2.00-1.47 (16H, m).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 166,tert-butyl5-(4-(1-(1-(benzyloxycarbonyl)cyclooctyl)piperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-1(2H)-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate,was confirmed using ¹H NMR.

Substituted-Quinoxaline-Type Piperidine Compound 166: ¹H NMR: δ_(H) (300MHz, DMSO-d₆): 7.51-7.38 (7H, m), 7.18-7.15 (2H, m), 5.16 (2H, s), 4.45(1H, br), 4.00 (2H, br), 3.71 (2H, br), 3.50 (2H, br), 3.24 (2H, d,J=11.1 Hz), 2.76 (2H, d, J=9.3 Hz), 2.33 (2H, t, J=10.8 Hz), 2.01-1.47(16H, m).

In a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 5 in Example 7, Substituted-Quinoxaline-TypePiperidine Compound 167, benzyl1-(4-(3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)cyclooctanecarboxylate,was prepared from Substituted-Quinoxaline-Type Piperidine Compound 166(yield 90%) then, in a manner similar to the removal of the benzyl groupin Example 18, Substituted-Quinoxaline-Type Piperidine Compound 168 wasprepared from Substituted-Quinoxaline-Type Piperidine Compound 167(yield 27%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 168,1-(4-(3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)cyclooctanecarboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 168: ¹H NMR: δ_(H) (300MHz, DCl/D₂O): 7.53 (2H, d, J=8.1 Hz), 7.34 (1H, t, J=8.1 Hz), 7.23 (1H,t, J=8.1 Hz), 4.38 (5H, br), 3.57 (4H, d, J=5.7 Hz), 3.35-3.22 (6H, m),3.07-2.99 (2H, m), 2.23-2.00 (6H, m), 1.54 (6H, br), 1.24 (4H, br);LC/MS (100%, t_(r)=0.83 min): m/z=494.2 [M+H]⁺ (Calc: 493.3).

In a manner similar to the removal of the benzyl group in Example 18,Substituted-Quinoxaline-Type Piperidine Compound 169 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 166 (yield 81%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 169,14443-(5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)cyclooctanecarboxylicacid, was confirmed using ¹H NMR.

Substituted-Quinoxaline-Type Piperidine Compound 169: ¹H NMR: δ_(H) (300MHz, CD₃OD): 7.55-7.48 (2H, m), 7.23-7.19 (2H, m), 4.16 (2H, br), 3.90(2H, br), 3.68-3.62 (4H, m), 3.30-3.22 (4H, m), 2.98 (2H, br), 2.24-2.00(6H, m), 1.74-1.47 (21H, m).

At a temperature of about 25° C., a reaction mixture ofSubstituted-Quinoxaline-Type Piperidine Compound 169 (150 mg, 0.25 mmol,1 eq), NH₄Cl (16 mg, 0.30 mmol, 1.2 eq), DIEA (51 μL, 0.30 mmol, 1.2eq), HOBT (38 mg, 0.28 mmol, 1.1 eq, Acros Organics), WSCI (54 mg, 0.28mmol, 1.1 eq, Sigma-Aldrich), and DMAP (5.6 mg, 0.05 mmol, 0.2 eq) inDMF (3 mL) was stirred for 48 hr. Thereafter, the mixture was pouredinto water (20 mL) and extracted twice with CHCl₃ (30 mL for eachextraction). The organic portions were combined, washed with saturatedaqueous NaHCO₃, washed with water, dried (MgSO₄), and concentrated underreduced pressure to provide a pale yellow amorphous solid.

The solid was chromatographed with a silica gel column eluted with agradient of from 100%:0% CHCl₃:MeOH to 97%:3% CHCl₃:MeOH to provide 40mg of Substituted-Quinoxaline-Type Piperidine Compound 170 as acolorless amorphous solid (yield 27%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 170,tert-butyl5-(4-(1-(1-carbamoylcyclooctyl)piperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-1(2H)-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate,was confirmed using ¹H NMR.

Substituted-Quinoxaline-Type Piperidine Compound 170: ¹H NMR: δ_(H) (300MHz, DMSO-d₆): 7.71 (1H, br), 7.35-7.32 (1H, m), 7.16-7.12 (2H, m), 6.96(1H, m), 3.99 (2H, br), 3.73 (1H, br), 3.50 (2H, br), 3.18-3.15 (2H, m),2.99-2.89 (2H, m), 2.68-2.65 (2H, m), 2.38-2.31 (2H, m), 1.96-1.39 (28H,m).

In a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 5 in Example 7, Substituted-Quinoxaline-TypePiperidine Compound 171 was prepared from Substituted-Quinoxaline-TypePiperidine Compound 170 (yield 41%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 171,1-(4-(3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl)piperidin-1-yl)cyclooctanecarboxamide,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 171: ¹H NMR: δ_(H) (300MHz, DMSO-d₆): 7.70 (1H, br), 7.36-7.33 (1H, m), 7.16-7.13 (3H, m), 6.96(1H, s), 4.65 (1H, br), 3.99 (2H, br), 3.50 (2H, br), 3.02-2.96 (4H, m),2.80-2.66 (6H, m), 2.34 (2H, t, J=11.4 Hz), 2.00-1.95 (2H, m), 1.83-1.78(2H, m), 1.62-1.39 (12H, m); LC/MS (100%, t_(r)=0.78 min): m/z=493.2[M+H]⁺ (Calc: 492.7).

5.30 Example 30

At a temperature of about 25° C., K₂CO₃ (228 mg, 1.65 mmol, 0.1 eq) wasadded to a mixture of the compound of formula HA (1-adamantylamine, 5.02g, 33.2 mmol), ethanol (12 mL), and water (12 mL). Then, a mixture ofthe compound of formula GF (5.47 g, 16.5 mmol), ethanol (13 mL), andwater (13 mL) was added. The resulting reaction mixture was refluxed for3 h. Thereafter, the mixture was poured into water and extracted withEtOAc. The organic portion was dried (Na₂SO₄) then concentrated underreduced pressure to provide a residue. The residue was chromatographedwith a silica gel column eluted with 97%:3% CHCl₃:MeOH to provide 1.97 gof the compound of formula HB as a colorless solid (yield 51%).

The identity of the compound of formula BE,1-adamantan-1-yl-piperidin-4-one, was confirmed using ¹H NMR.

Compound HB: ¹H NMR: δ_(H) (300 MHz, CDCl₃): 2.96 (4H, s), 2.46 (4H, s),2.14 (3H, s), 1.79-1.62 (14H, m).

The compound of formula HC was prepared in a manner similar to thepreparation of the compound of formula AB in Example 1 except tert-butyl2-aminophenylcarbamate was used in place of 1,2-phenylenediamine (yield60%).

The identity of the compound of formula HC,[2-(1-adamantan-1-yl-piperidin-4-yl-amino)-phenyl]-carbamic acidtert-butyl ester, was confirmed using ¹H NMR and LC/MS.

Compound HC: ¹H NMR: δ_(H) (400 MHz, DMSO-d₆): 8.32 (1H, s), 7.13 (1H,d, J=7.6 Hz), 6.96-6.92 (1H, m), 6.62 (1H, d, J=7.6 Hz), 6.54-6.50 (1H,m), 4.52 (1H, d, J=7.1 Hz), 3.18 (1H, dd, J=7.35, 3.30 Hz), 2.99 (2H, d,J=11.15 Hz), 2.25 (2H, t, J=10.14 Hz), 2.03 (3H, s), 1.91 (2H, d,J=11.66 Hz), 1.65-1.54 (12H, m), 1.43 (9H, s), 1.30 (2H, q, J=9.97 Hz);LC/MS: m/z=426 [M+H]⁺ (Calc: 425.3).

In a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 5 in Example 7, the compound of formula HD wasprepared from the compound of formula HC (yield >98%).

The identity of the compound of formula HD,N-(1-adamantan-1-yl-piperidin-4-yl)benzene-1,2-diamine, was confirmedusing ¹H NMR and LC/MS.

Compound HD: ¹H NMR: δ_(H) (400 MHz, DMSO-d₆): 6.54-6.35 (4H, m), 4.45(2H, s), 4.05 (1H, d, J=7.6 Hz), 3.10 (3H, m), 2.20 (2H, s), 2.04 (3H,s), 1.93 (2H, d, J=10.65 Hz), 1.60 (12H, m), 1.31 (2H, br); LC/MS:m/z=325.8 [M+H]⁺ (Calc: 325.3).

In a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 120 from Substituted-Quinoxaline-Type PiperidineCompound 74 in Example 21, Substituted-Quinoxaline-Type PiperidineCompound 164 was prepared from the compound of formula HD (yield 20%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 164,4-(1-adamantan-1-yl)-piperidin-4-yl)-3-oxo-3,4-dihydro-quinoxaline-2-carboxylicacid ethyl ester, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 164: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.90 (2H, m), 7.76-7.71 (1H, m), 7.44 (1H, t, J=7.6 Hz),4.73 (1H, br), 4.37 (2H, q, J=7.1 Hz), 3.25 (2H, m), 2.59 (2H, m), 2.28(2H, t, J=10.9 Hz), 2.06 (3H, s), 1.69-1.57 (14H, m), 1.32 (3H, t, J=7.1Hz); LC/MS: m/z=435.9 [M+H]⁺ (Calc: 435.3).

Substituted-Quinoxaline-Type Piperidine Compound 134 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 164 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 91%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 134,4-(1-adamantan-1-yl-piperidin-4-yl)-3-oxo-3,4-dihydro-quinoxalin-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 134: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 8.11 (1H, br), 7.70 (1H, dd, J=8.11, 1.52 Hz), 7.51 (1H,t, J=7.35 Hz), 7.32 (1H, t, J=7.6 Hz), 5.15 (1H, br), 3.67 (2H, s),3.19-3.02 (6H, m), 2.17 (3H, s), 1.92 (7H, m), 1.65 (6H, s); LC/MS(100%, t_(r)=1.33 min): m/z=408.3 [M+H]⁺ (Calc: 407.5).

5.31 Example 31

Under a nitrogen atmosphere, to a mixture of the compound of formula GA(28 g, 222 mmol) and Et₂O (500 mL) at a temperature of −40° C. was addedmethylmagnesium bromide (89 mL, 266 mmol, Sigma-Aldrich). The resultingreaction mixture was stirred for 4 h as its temperature warmed from -40°C. to 0° C. then stirred an additional 1.5 h as its temperature warmedfrom 0° C. to about 25° C. Thereafter, saturated aqueous NH₄Cl wasadded, the mixture was neutralized with 2N aqueous HCl to adjust the pHinto the range between 5-6, and the mixture was extracted 3 times withEt₂O (400 mL for each extraction). The organic portions were combined,dried (Na₂SO₄), filtered, and concentrated under reduced pressure toprovide the compound of formula IA, 1-methylcyclooctanol, as a colorlessoil. Acetic acid (29.3 mL, 512 mmol) was added to a mixture of thecompound of formula IA (26 g, 183 mmol) and 2-chloroacetonitrile (23.20mL, 365 mmol, Sigma-Aldrich) and the resulting reaction mixture wascooled to a temperature in the range of from 0° C. to 3° C. H₂SO₄ (29.2mL, 548 mmol) was added dropwise over 1 h such that the temperature waskept below 10° C. Thereafter, the reaction mixture was warmed to atemperature of about 25° C. and stirred for 1.5 hrs. After quencing withice-water (400 mL), the mixture was neutralized with a 30% NaOH aqueoussolution to adjust the pH into the range between 7-8; a whiteprecipitate formed. The precipitate was collected by filtration, washedtwice with water (100 mL for each wash), and dried under reducedpressure at 60° C. for 6 h to provide 27 g of the compound of formula IB(yield 56%).

The identity of the compound of formula IB,2-chloro-N-(1-methylcyclooctyl)acetamide, was confirmed using ¹H NMR.

Compound IB: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 6.28 (1H, s), 3.95 (2H, s),2.05-2.00 (2H, m), 1.72 (2H, td, J=10.01, 4.06 Hz), 1.57 (11.2H, m),1.41 (3H, s).

Under a nitrogen atmosphere, to a mixture of the compound of formula IB(27 g, 124 mmol) and ethanol (240 mL) at a temperature of about 25° C.was added thiourea (11.30 g, 148 mmol, Sigma-Aldrich) and acetic acid(45 mL) The resulting reaction mixture was warmed to 110° C. and stirredfor 7 h. After cooling the mixture to a temperature of about 25° C. andquencing with water (700 mL), the white precipitate that formed wasfiltered off. The filtrate was neutralized with a 30% NaOH aqueoussolution, its pH was adjusted to pH14, it was washed twice withn-hexane:H₂O (400 mL for each wash), dried (Na₂SO₄), and concentratedunder reduced pressure to provide 17 g of the compound of formula IC asa pale yellow oil (yield 97%).

The identity of the compound of formula IC, 1-methylcyclooctanamine, wasconfirmed using ¹H NMR.

Compound IC: ¹H NMR: δ_(H) (300 MHz, CDCl₃): 1.58-1.47 (14H, m),1.26-1.21 (2H, m), 1.07 (3H, s).

The compound of formula IE was prepared in a manner similar to thepreparation of the compound of formula DB in Example 13 except1-methylpiperidin-4-one (ID), Sigma-Aldrich) was used in place oftropinone and methyl iodide was used in place of dimethyl sulfate.

In a manner similar to Example 30, Substituted-Quinoxaline-TypePiperidine Compound 234 was prepared except that the compound of formulaIE was used in place of the compound of formula GF and the compound offormula IC was used in place of the compound of formula HA.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 234,ethyl4-(1-(1-methylcyclooctyl)piperidin-4-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 234: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.93 (1H, dd, J=8.11, 1.01 Hz), 7.76 (1H, d, J=4.56 Hz),7.61 (1H, dd, J=11.66, 4.06 Hz), 7.36 (1H, t, J=7.6 Hz), 4.90 (1H, br),4.50 (2H, q, J=7.1 Hz), 3.15 (2H, d, J=11.66 Hz), 2.78 (2H, dd, J=5.07,3.55 Hz), 2.23 (2H, t, J=11.41 Hz), 1.86-1.24 (20H, m), 0.84 (3H, d,J=10.65 Hz); LC/MS: m/z=426 [M+H]⁺ (Calc: 425).

At a temperature of about 25° C., to a mixture ofSubstituted-Quinoxaline-Type Piperidine Compound 234 (188 mg, 0.442mmol) and ethanol (8 mL) was added 2N aqueous NaOH (0.663 mL, 1.325mmol) and the reaction mixture was stirred for 45 min. Thereafter, themixture was concentrated under reduced pressure to provide a residue.The residue was diluted with water, neutralized with 2N aqueous HCl(0.663 mL), and extracted with CHCl₃:H₂O to provide an emulsion that wasconcentrated under reduced pressure to provide a second residue. Thesecond residue was diluted with CHCl₃, dried (MgSO₄), and concentratedunder reduced pressure to provide a pale yellow solid. The solid waswashed with 1:1 EtOAc:Et₂O, filtrated, and dried under reduced pressureat 70° C. for 12 h to provide a third residue. The third residue wasdiluted with 2N aqueous HCl (2 mL), heated, sonicated, and concentratedunder reduced pressure to provide an oil. The oil was dried underreduced pressure at 70° C. for 12 h to provide the hydrochloride ofSubstituted-Quinoxaline-Type Piperidine Compound 235 as a yellowamorphous solid.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 235,4-(1-(1-methylcyclooctyl)piperidin-4-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 235: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 8.28 (1H, br), 7.84 (1H, s), 7.65 (1H, s), 7.44 (1H, s),5.32 (1H, s), 3.63 (4H, d, J=2.53 Hz), 2.14-1.36 (21H, m); LC/MS (100%,t_(r)=1.40 min): m/z=398 [M+H]⁺ (Calc: 397).

In a manner similar to that described above, the compound of formula IKwas prepared from the compound of formula GA except that ethylmagnesiumbromide (Sigma-Aldrich) was used in place of methylmagnesium bromide(yield 20%).

The identity of the compound of formula IK, 1-ethylcyclooctanamine, wasconfirmed using ¹H NMR.

Compound IK: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 1.63-1.34 (16H, m), 1.10(2H, s), 0.86 (3H, t, J=7.6 Hz).

In a manner similar to that described above,Substituted-Quinoxaline-Type Piperidine Compound 236 was prepared fromthe compound of formula IE except that the compound of formula IK wasused in place of the compound of formula IC.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 236,ethyl4-(1-(1-ethylcyclooctyl)piperidin-4-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 236: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.93 (1H, d, J=8.11 Hz), 7.76 (1H, d, J=1.01 Hz), 7.61 (1H,dd, J=7.86, 6.84 Hz), 7.35 (1H, t, J=7.6 Hz), 4.94 (1H, br), 4.50 (2H,ddd, J=14.19, 7.10, 1.52 Hz), 3.15 (2H, d, J=10.65 Hz), 2.71 (2H, br),2.34 (2H, t, J=11.41 Hz), 1.83-1.39 (18H, m), 0.86 (3H, t, J=7.35 Hz);LC/MS: m/z=440 [M+H]⁺ (Calc: 439).

2N aqueous NaOH (0.114 mL, 0.227 mmol) was added to a mixture ofSubstituted-Quinoxaline-Type Piperidine Compound 236 (100 mg, 0.227mmol) and ethanol (2 mL) at 25° C. The resulting reaction mixture wasstirred at a temperature of about 25° C. for 2 h. After concentrationunder reduced pressure, the resulting solid was triturated with Et₂O,filtered, and dried under reduced pressure at 80° C. to provide 98 mg ofthe sodium salt of Substituted-Quinoxaline-Type Piperidine Compound 237as a pale yellow solid (yield >98%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 237,4-(1-(1-ethylcyclooctyl)piperidin-4-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 237: ¹H NMR: δ_(H) (400MHz, CD₃OD): 7.82 (2H, dd, J=28.13, 7.86 Hz), 7.58 (1H, dd, J=8.36, 7.35Hz), 7.34 (1H, t, J=7.6 Hz), 3.19 (2H, d, J=10.65 Hz), 2.80 (2H, d,J=10.65 Hz), 2.40 (2H, t, J=11.41 Hz), 1.89-1.46 (18H, m), 0.89 (3H, t,J=7.35 Hz); LC/MS (100%, t_(r)=1.57 min): m/z=411 [M+H]⁺ (Calc: 410).

In a manner similar to that described above, the compound of formula INwas prepared from the compound of formula GA except that propylmagnesiumbromide (Sigma-Aldrich) was used in place of methylmagnesium bromide(yield 26%).

The identity of the compound of formula IN, 1-propylcyclooctanamine, wasconfirmed using ¹H NMR.

Compound IN: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 1.63-1.19 (20H, m), 0.92(3H, t, J=5.83 Hz).

In a manner similar to that described above,Substituted-Quinoxaline-Type Piperidine Compound 238 was prepared fromthe compound of formula IE except that the compound of formula IN wasused in place of the compound of formula IC.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 238,ethyl3-oxo-4-(1-(1-propylcyclooctyl)piperidin-4-yl)-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 238: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.93 (1H, d, J=7.6 Hz), 7.75 (1H, dd, J=3.80, 1.77 Hz),7.63-7.59 (1H, m), 7.35 (1H, t, J=7.6 Hz), 4.93 (1H, br), 4.53-4.48 (2H,m), 3.54 (1H, br), 3.14 (2H, d, J=11.15 Hz), 2.73 (2H, ddd, J=18.38,11.03, 3.93 Hz), 2.33 (2H, t, J=11.41 Hz), 1.80-1.24 (20H, m), 0.91 (3H,d, J=12.67 Hz); LC/MS: m/z=454 [M+H]⁺ (Calc: 453).

In a manner similar to that described above, the sodium salt ofSubstituted-Quinoxaline-Type Piperidine Compound 239 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 238 (yield 88%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 239,3-oxo-4-(1-(1-propylcyclooctyl)piperidin-4-yl)-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 239: ¹H NMR: δ_(H) (400MHz, CD₃OD): 7.86-7.77 (2H, m), 7.60-7.56 (1H, m), 7.34 (1H, t, J=7.6Hz), 3.18 (2H, d, J=11.15 Hz), 2.79 (2H, d, J=9.63 Hz), 2.39 (2H, t,J=11.41 Hz), 1.90-1.29 (20H, m), 0.91 (3H, t, J=5.83 Hz); LC/MS (96%,t_(r)=1.82 min): m/z=425 [M+H]⁺ (Calc: 424).

5.32 Example 32

The compound of formula JA,(endo)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine, was prepared by amethod known to those in the art, e.g., M. Allegretti et al.,Tetrahedron Let., 58:5669-5674 (2002). K₂CO₃ (9.12 g, 66 mmol) was addedto a mixture of the dihydrochloride of the compound of formula JA (4.69g, 22 mmol) and 1-fluoro-2-nitrobenzene (3.10 g, 22 mmol, Sigma-Aldrich)in THF (30 mL) and water (10 mL). The resulting reaction mixture wasrefluxed for 15 h. After cooling to a temperature of about 25° C. andquenching with water (50 mL), the mixture was extracted twice withCHCl₃. The organic portions were combined, dried (MgSO₄), andconcentrated under reduced pressure to provide a residue. The residuewas chromatographed with an amino-silica gel column eluted with agradient of from 30%:70% EtOAc:n-hexane to 100%:0% EtOAc:n-hexane toprovide 5.5 g of the compound of formula JB as an orange solid (yield93%).

The identity of the compound of formula JB,(endo)-8-methyl-N-(2-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-amine, wasconfirmed using ¹H NMR.

Compound JB: ¹H NMR: δ_(H) (300 MHz, CDCl₃): 8.68 (1H, d, J=6.1 Hz),8.18 (1H, d, J=8.6 Hz), 7.41 (1H, dd, J=8.4, 7.4 Hz), 6.73 (1H, d, J=8.6Hz), 6.61 (1H, dd, J=8.4, 7.4 Hz), 3.81 (1H, q, J=6.8 Hz), 3.19 (2H, s),2.30-2.27 (5H, m), 2.15-2.10 (2H, m), 1.96-1.94 (2H, m), 1.81 (2H, d,J=14.7 Hz).

After cooling a mixture of the compound of formula JB (5.49 g, 20.4mmol) and CHCl₃ (55 mL) to a temperature of 0° C., 1-chloroethylchloroformate (3.3 mL, 30.6 mmol, Sigma-Aldrich) was added and thereaction mixture was refluxed for 2.5 h. After cooling to a temperatureof about 25° C., the mixture was concentrated under reduced pressure toprovide a residue. The residue was mixed with MeOH (55 mL) to form asecond reaction mixture which was refluxed for 5 h. After cooling to atemperature of about 25° C., the mixture was diluted with EtOAc (100 mL)and cooled further to 0° C. where a precipitate formed. The precipitatewas filtered, washed with EtOAc, and dried at 45° C. under reducedpressure to provide 4.66 g of the hydrochloride of the compound offormula JC as a yellow solid (yield 81%).

The identity of the compound of formula JC,(endo)-N-(2-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-amine, was confirmedusing ¹H NMR.

Compound JC: ¹H NMR: δ_(H) (300 MHz, DMSO-d₆): 9.22 (2H, br s), 8.39(1H, d, J=6.6 Hz), 8.11 (1H, dd, J=8.6, 1.5 Hz), 7.60-7.55 (1H, m), 7.02(1H, d, J=8.6 Hz), 6.75 (1H, t, J=7.9 Hz), 4.08-3.98 (3H, m), 2.52-2.49(4H, m), 2.47-2.40 (2H, m), 2.17-2.08 (4H, m), 2.01 (2H, d, J=15.7 Hz).

A reaction mixture of the compound of formula JC (3.41 g, 12.0 mmol),(Z)-3-bromocyclooct-1-ene (3.40 g, 18.0 mmol, Sigma-Aldrich), K₂CO₃(4.98 g, 36.0 mmol), and acetonitrile (120 mL) was refluxed for 4.5 h.After cooling to a temperature of about 25° C. and quenching with water(100 mL), the mixture was extracted twice with CHCl₃. The organicportions were combined, dried (MgSO₄), and concentrated under reducedpressure to provide a residue. The residue was recrystallized fromEtOAc:n-hexane to provide 3.85 g of the compound of formula JD as anorange solid (yield 97%).

The identity of the compound of formula JD,(endo)-8-((Z)-cyclooct-2-enyl)-N-(2-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-amine,was confirmed using ¹H NMR.

Compound JD: ¹H NMR: δ_(H) (300 MHz, CDCl₃): 8.73 (1H, d, J=6.6 Hz),8.19 (1H, dd, J=8.6, 1.5 Hz), 7.42-7.39 (1H, m), 6.73 (1H, d, J=8.6 Hz),6.61 (1H, t, J=7.6 Hz), 5.77 (1H, dd, J=18.8, 8.1 Hz), 5.38 (1H, t,J=9.4 Hz), 3.87 (1H, q, J=6.6 Hz), 3.57-3.41 (3H, m), 2.33-1.26 (18H,m).

Under a hydrogen atmosphere, a mixture of the compound of formula JD(13.8 g, 38.8 mmol), 10% palladium on carbon (50 mg, 0.047 mmol), MeOH(10 mL), and EtOAc (10 mL) was stirred at a temperature of about 25° C.for 5 h. After the Pd/C was filtered off through cellulose powder, themixture was washed with MeOH (50 mL) and concentrated under reducedpressure to provide the compound of formula JE,N¹-((endo)-8-((Z)-cyclooct-2-enyl)-8-azabicyclo[3.2.1]octan-3-yl)benzene-1,2-diamine,as a brown solid. In a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 70 from the compound offormula AB in Example 12, Substituted-Quinoxaline-Type PiperidineCompound 159 was prepared from diethyl 2-oxomalonate and the compound offormula JE (yield 20% for two steps).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 159,ethyl4-((endo)-8-((Z)-cyclooct-2-enyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 159: ¹H NMR: δ_(H) (300MHz, CDCl₃): 7.88 (1H, dd, J=8.11, 1.52 Hz), 7.79-7.75 (1H, m), 7.66(1H, d, J=9.12 Hz), 7.44 (1H, t, J=7.86 Hz), 5.72 (1H, dd, J=18.25, 8.11Hz), 5.38 (2H, t, J=9.63 Hz), 4.41-4.34 (2H, m), 3.71 (1H, t, J=7.6 Hz),3.51 (1H, t, J=7.86 Hz), 3.19 (1H, dd, J=15.97, 8.36 Hz), 2.30-2.22 (2H,m), 2.13-1.55 (14H, m), 1.39-1.18 (8H, m); LC/MS: m/z=435.9 [M+H]⁺(Calc: 435.3).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound135 was prepared from Substituted-Quinoxaline-Type Piperidine Compound159 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield73%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 135,4-((endo)-8-((Z)-cyclooct-2-enyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 135: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 11.05 (1H, s), 8.09 (1H, d, J=8.11 Hz), 7.90 (1H, dd,J=7.86, 1.27 Hz), 7.76 (1H, t, J=7.35 Hz), 7.47 (1H, t, J=7.6 Hz), 6.05(2H, dt, J=23.66, 7.98 Hz), 5.85 (1H, t, J=9.63 Hz), 4.37 (1H, t, J=7.1Hz), 4.01 (1H, s), 3.85 (1H, s), 2.63 (2H, dd, J=21.54, 9.38 Hz),2.36-1.91 (9H, m), 1.72 (3H, m), 1.31 (3H, m); LC/MS (98%, t_(r)=1.31min): m/z=408.2 [M+H]⁺ (Calc: 407.5).

Alternatively, Substituted-Quinoxaline-Type Piperidine Compound 159 wasprepared by the following route.

To a mixture of the compound of formula JC (2012 mg, 7.09 mmol) andCH₂Cl₂ (20 mL) at 0° C. was added TEA (2.95 mL, 21.3 mmol) anddi-tert-butyl dicarbonate (1.81 μL, 7.80 mmol). The resulting reactionmixture was stirred at 0° C. for 2 h then concentrated under reducedpressure, diluted with water (20 mL), and extracted three times withEtOAc (20 mL for each extraction). The organic portions were combined,washed with saturated aqueous NaHCO₃ (10 mL), washed with saturatedaqueous NaCl (10 mL), dried (MgSO₄), and concentrated under reducedpressure to provide an oil. The oil was chromatographed with a silicagel column eluted with 2:1 hexanes:EtOAc to provide 2421 mg of thecompound of formula JF as a yellow amorphous solid (yield 98%).

The identity of the compound of formula JF, (endo)-tert-butyl3-(2-nitrophenylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate, wasconfirmed using ¹H NMR and LC/MS.

Compound JF: ¹H NMR: δ_(H) (400 MHz, DMSO): 8.60 (1H, d, J=8.0 Hz), 8.10(1H, d, J=8.0 Hz), 7.55 (1H, t, J=8.0 Hz), 6.96 (1H, d, J=8.0 Hz), 6.71(1H, t, J=8.0 Hz), 4.12 (2H, m), 4.03 (1H, m), 2.20 (2H, m), 2.06-1.90(4H, m), 1.80 (2H, m), 1.43 (9H, s); LC/MS (100%, t_(r)=2.99 min):m/z=348 [M+H]⁺ (Calc: 347.2).

In a manner similar to the preparation of the compound of formula CC inExample 6, the compound of formula JG was prepared except that thecompound of formula JF was used in place of the compound of formula CB(yield 85%).

The identity of the compound of formula JG, (endo)-tert-butyl3-(2-aminophenylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate, wasconfirmed using ¹H NMR and LC/MS.

Compound JG: ¹H NMR: δ_(H) (400 MHz, DMSO): 6.58 (1H, d, J=8.0 Hz), 6.50(2H, m), 6.34 (1H, d, J=8.0 Hz), 4.49 (2H, s), 4.25 (1H, s), 4.03 (2H,m), 3.59 (1H, m), 2.13 (2H, d, J=8.0 Hz), 2.04 (2H, m), 1.90-1.70 (4H,m), 1.42 (9H, s); LC/MS (100%, t_(r)=1.91 min): m/z=318 [M+H]⁺ (Calc:317.2).

In a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 70 from the compound of formula AB in Example 12,Substituted-Quinoxaline-Type Piperidine Compound 267 was prepared fromdiethyl 2-oxomalonate and the compound of formula JG (yield 92%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 267,ethyl4-((endo)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 267: ¹H NMR: δ_(H) (400MHz, DMSO): 7.90 (1H, d, J=8.0 Hz), 7.77 (1H, t, J=8.0 Hz), 7.57 (1H,J=8.0 Hz), 7.46 (1H, t, J=8.0 Hz), 4.36 (2H, q, J=8.0 Hz), 4.27 (2H, m),2.37 (2H, m), 2.18 (2H, m), 2.02 (2H, m), 1.89 (2H, m), 1.48 (9H, s),1.33 (3H, t, J=8.0 Hz); LC/MS (100%, t_(r)=2.48 min): m/z=428 [M+H]⁺(Calc: 427.2).

In a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 5 in Example 7, Substituted-Quinoxaline-TypePiperidine Compound 267 was treated with 4N HCl in dioxane to remove theBOC group; after concentration under reduced pressure, the resultingsolid was reacted with (Z)-3-bromocyclooct-1-ene in a manner similar tothe preparation of the compound of formula JD described above to provideSubstituted-Quinoxalinc-Type Piperidine Compound 159 (yield 68% for twosteps).

Under a hydrogen atmosphere at a pressure of 4 Kgf/cm², a mixture ofSubstituted-Quinoxaline-Type Piperidine Compound 159 (124 mg, 0.285mmol), 20% Pd(OH)₂ (24 mg, Sigma-Aldrich), and MeOH (12 mL) was stirredat 50° C. for 8 h. After the Pd(OH)₂ was filtered off, the filtrate waswashed with EtOAc and concentrated under reduced pressure to provideSubstituted-Quinoxaline-Type Piperidine Compound 389, ethyl4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-2-carboxylate.

A mixture of the above Substituted-Quinoxaline-Type Piperidine Compound389 and xylene (4 mL) was stirred at 130° C. for 5 days. Afterconcentration under reduced pressure, the residue was chromatographedwith a silica gel column eluted with 10:1 CHCl₃:MeOH to provide 113 mgof Substituted-Quinoxaline-Type Piperidine Compound 153 as a yellowsolid (yield 91% for two steps).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 153 wasconfirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 153: ¹H NMR: δ_(H) (400MHz, DMSO): 7.88 (1H, d, J=8.0 Hz), 7.77 (1H, t, J=8.0 Hz), 7.63 (1H, d,J=8.0 Hz), 7.44 (1H, t, J=8.0 Hz), 5.20 (1H, br), 4.37 (2H, q, J=8.0Hz), 3.63 (2H, m), 2.36 (1H, m), 2.26 (2H, m), 2.06 (2H, m), 1.99 (2H,m), 1.85-1.20 (16H, m), 1.32 (3H, t, J=8.0 Hz); LC/MS (100%, t_(r)=1.63min): m/z=438 [M+H]⁺ (Calc: 437.3).

In a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 5 in Example 7, Substituted-Quinoxaline-TypePiperidine Compound 268 was prepared by treatingSubstituted-Quinoxaline-Type Piperidine Compound 267 with 4N HCl indioxane to remove the BOC group (yield >98%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 268,ethyl4-((endo)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 268: LC/MS: m/z=328[M+H]⁺ (Calc: 327).

In a manner similar to the preparation of the compound of formula JDdescribed above, Substituted-Quinoxaline-Type Piperidine Compound 269was prepared except that the compound of formula JH was used in place of(Z)-3-bromocyclooct-1-ene (yield 39%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 269,ethyl4-((endo)-8-(1,2-dihydroacenaphthylen-1-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 269: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.90 (1H, d, J=7.6 Hz), 7.68 (2H, dd, J=27.37, 8.11 Hz),7.58-7.47 (5H, m), 7.32 (2H, dd, J=11.91, 6.84 Hz), 4.54-4.47 (3H, m),4.08 (1H, br), 3.64-3.51 (2H, m), 3.27 (1H, d, J=16.73 Hz), 2.33-1.98(9H, m), 1.58 (3H, s), 1.44 (3H, t, J=7.1 Hz); LC/MS: m/z=480 [M+H]⁺(Calc: 479).

Substituted-Quinoxaline-Type Piperidine Compound 270 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 269 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 84%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 270,4-((endo)-8-(1,2-dihydroacenaphthylen-1-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 270: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.83-7.52 (8H, m), 7.42-7.37 (2H, m), 5.18 (1H, s), 4.73(1H, brz), 4.21 (1H, br), 3.84-3.82 (1H, m), 3.65 (2H, br), 2.33-1.99(8H, m); LC/MS (100%, t_(r)=1.45 min): m/z=452 [M+H]⁺ (Calc: 451).

The compound of formula JH was prepared as follows:

Under a nitrogen atmosphere and at a temperature of about 25° C., a 1Msolution of tribromophosphine in CH₂Cl₂ (2.350 mL, 2.350 mmol,Sigma-Aldrich) was added to a suspension of1,2-dihydroacenaphthylen-1-ol (1000 mg, 5.88 mmol, Sigma-Aldrich) indiethyl ether (8 mL). The resulting reaction mixture was stirred at atemperature of about 25° C. for 30 min; a yellow precipitate formed.After quenching with saturated aqueous NaHCO₃, the pH was adjusted to bewithin the range of from about 7 to about 8. Thereafter, the mixture wasextracted twice with EtOAc:water (70 mL for each extraction), dried(MgSO₄), concentrated under reduced pressure, and dried to provide 1350mg of the compound of formula JH, 1-bromo-1,2-dihydroacenaphthylene, asa pale yellow solid (yield 99%).

5.33 Example 33

Under a nitrogen atmosphere at a temperature of about 25° C., K₂CO₃(1218 mg, 8.81 mmol), sodium iodide (52.8 mg, 0.352 mmol), and(bromomethylene)dibenzene (523 mg, 2.115 mmol, Sigma-Aldrich) were addedto a mixture of the compound of formula JC (500 mg, 1.762 mmol) andacetonitrile (10 mL). The resulting reaction mixture was heated withstirring at 90° C. for 1 h. The reaction mixture was diluted with water(5 mL), extracted twice with CHCl₃ (50 mL for each extraction), washedwith brine, dried (MgSO₄), and concentrated under reduced pressure toprovide a yellow oil. The oil was chromatographed with an amino-silicagel column eluted with a gradient of from 0%:100% EtOAc:n-hexane to20%:80% EtOAc:n-hexane to provide 464 mg of the compound of formula KAas an orange solid (yield 64%).

The identity of the compound of formula KA,(endo)-8-benzhydryl-N-(2-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-amine,was confirmed using ¹H NMR and LC/MS.

Compound KA: ¹H NMR: δ_(H) (300 MHz, DMSO-d₆): 8.58 (1H, d, J=7.1 Hz),8.07 (1H, dd, J=8.62, 1.52 Hz), 7.54 (5H, dd, J=9.89, 4.31 Hz), 7.29(4H, t, J=7.6 Hz), 7.17 (2H, t, J=7.35 Hz), 6.93 (1H, d, J=8.62 Hz),6.70-6.65 (1H, m), 4.62 (1H, s), 4.02 (1H, dd, J=6.84, 4.82 Hz), 3.07(2H, s), 2.25 (2H, m), 2.10 (2H, m), 1.83 (2H, dd, J=14.70, 6.59 Hz),1.65 (2H, d, J=13.69 Hz); LC/MS: m/z=413.8 [M+H]⁺ (Calc: 413.2).

In a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 135 from the compound of formula KD in Example 32,the compound of formula KB was prepared from the compound of formula KA(yield 90%), Substituted-Quinoxaline-Type Piperidine Compound 160 wasprepared from the compound of formula KB and diethyl 2-oxomalonate(yield 49%), and the hydrochloride of Substituted-Quinoxaline-TypePiperidine Compound 136 was prepared from Substituted-Quinoxaline-TypePiperidine Compound 160 (yield 70%).

The identity of the compound of formula KB,N¹-((endo)-8-benzhydryl-8-azabicyclo[3.2.1]octan-3-yl)benzene-1,2-diamine,was confirmed using ¹H NMR and LC/MS.

Compound KB: ¹H NMR: δ_(H) (300 MHz, DMSO-d₆): 7.52 (2H, d, J=7.6 Hz),7.30-7.14 (8H, m), 6.58-6.29 (4H, m), 4.44 (2H, s), 4.12 (1H, s), 3.58(1H, m), 2.99 (1H, s), 2.14-1.91 (5H, m), 1.65 (3H, m); LC/MS: m/z=383.9[M+H]⁺ (Calc: 383.2).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 160,ethyl4-((endo)-8-benzhydryl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 160: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.91-7.16 (14H, m), 4.47 (1H, s), 4.36 (2H, q, J=6.9 Hz),2.52 (1H, m), 2.33-1.99 (6H, m), 1.75 (2H, m), 1.33 (3H, t, J=6.9 Hz);LC/MS: m/z=494.0 [M+H]⁺ (Calc: 493.2).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 136,4-((endo)-8-benzhydryl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 136: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 14.02 (0.7H, br), 10.95 (0.3H, br), 8.15-7.19 (14H, m),6.19 (0.3H, br), 5.42 (0.711, br), 4.47 (0.4H, s), 3.77 (0.6H, s), 2.69(1H, m), 2.39-2.10 (6H, m), 1.77 (1H, s); LC/MS (96%, t_(r)=2.25 min):m/z=466.2 [M+H]⁺ (Calc: 465.5).

5.34 Example 34

At a temperature of 0° C., ethyl 2-bromoacetate (20.2 μL, 0.182 mmol)and K₂CO₃ (25.2 mg, 0.182 mmol) were added to a mixture ofSubstituted-Quinoxaline-Type Piperidine Compound 165 (70 mg, 0.165 mmol)in THF (3 mL). The resulting reaction mixture was stirred at 0° C. for 2h. After warming it to 50° C., the reaction mixture was stirred at 50°C. for 2 h. After cooling to about 25° C., the mixture was diluted withwater (10 mL) and extracted twice with EtOAc (10 mL for eachextraction). The organic portions were combined, washed with brine (10mL), dried (MgSO₄), and concentrated under reduced pressure to provide aresidue. The residue was chromatographed with a silica gel column elutedwith 10:1 CHCl₃:MeOH to provide 53 mg of Substituted-Quinoxaline-TypePiperidine Compound 163 as a white solid (yield 63%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 163,(S)-ethyl2-(1-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)pyrrolidin-3-ylamino)acetate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 163: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.55 (1H, m), 7.45 (1H, d, J=8 Hz), 7.10 (2H, m), 4.95 (1H,br), 4.20 (2H, q, J=8 Hz), 4.30-3.90 (3H, m), 3.82 (1H, m), 3.46 (2H,s), 3.43 (1H, m), 2.98 (2H, m), 2.79 (2H, m), 2.68 (1H, m), 2.44 (2H,m), 2.10 (1H, m), 2.00-1.40 (18H, m), 1.60 (3H, t, J=8 Hz); LC/MS (98%,t_(r)=1.08 min): m/z=510.2 [M+H]⁺ (Calc: 509.3).

Substituted-Quinoxaline-Type Piperidine Compound 112 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 163 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 96%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 112,(S)-2-(1-(4-(1-cyclooctylpiperidin-4-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)pyrrolidin-3-ylamino)aceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 112: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.97 (1H, br), 7.36 (1H, d, J=8 Hz), 7.17 (2H, m), 5.00(1H, br), 4.30-3.10 (9H, m), 2.20 (2H, m), 2.10 (3H, m), 1.92 (2H, d,J=4 Hz), 1.90-1.40 (16H, m); LC/MS (100%, t_(r)=1.07 min): m/z=482.2[M+H]⁺ (Calc: 481.3).

5.35 Example 35

A mixture of the compound of formula LA (10.00 g, 65.4 mmol, Trans WorldChemicals, Inc., Rockville, Md.) and the compound of formula EB (11.17g, 65.4 mmol) was refluxed in acetone (150 mL) for 3 h, cooled,filtered, washed twice with diethyl ether (30 mL for each wash), washedtwice with hexanes (30 mL for each wash), and dried under reducedpressure to provide 10 g of the compound of formula LB,9-methyl-9-benzyl-9-azabicyclo[3.3.1]nonan-3-one bromide, as white solid(yield 47%).

In a manner similar to Example 14, the endo:exo isomeric mixture of thecompound of formula LD,N¹-(9-cyclooctyl-9-azabicyclo[3.3.1]nonan-3-yl)benzene-1,2-diamine, wasprepared except that the compound of formula LB was used in place of thecompound of formula EC. Thereafter, Substituted-Quinoxaline-TypePiperidine Compound 240 was prepared from diethyl 2-oxomalonate in amanner similar to Example 12 except that the compound of formula LD wasused in place of the compound of formula AB (overall yield 7%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 240,ethyl4-((endo)-9-cyclooctyl-9-azabicyclo[3.3.1]nonan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR, LC/MS and LC.

Substituted-Quinoxaline-Type Piperidine Compound 240: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.92 (d, 1H, J=8.2 Hz), 7.58-7.66 (m, 2H), 7.36 (dd, 1H,J=8.1, 8.2 Hz), 5.16 (br, 1H), 4.52 (t, 2H, J=7.0 Hz), 3.48-3.53 (m,2H), 3.02-3.06 (m, 1H), 2.72-2.74 (m, 2H), 2.38-2.44 (m, 1H), 1.98-2.04(m, 2H), 1.4-1.8 (m, 25H), 1.12-1.15 (m, 2H); LC/MS (98.7%, t_(r)=7.534min): m/z=452.7 [M+H]⁺ (Calc: 451.6); LC (SiO₂) 1:2 then 3:1Et₂O:hexanes: Rf=0.5 with UV detection, Dragendorffs reagent.

In a manner similar to Example 7, the hydrochloride ofSubstituted-Quinoxaline-Type Piperidine Compound 241 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 240 (yield 40%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 241,4-((endo)-9-cyclooctyl-9-azabicyclo[3.3.1]nonan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 241: ¹H NMR: δ_(H) (400MHz, 1:3 CDCl₃:CD₃OD): 8.45 (d, 1H, J=8.8 Hz), 8.02 (dd, 1H, J=1.5, 8.1Hz), 7.82-7.86 (m, 1H), 7.5 (dd, 1H, 7.5, 7.9 Hz), 5.96-6.04 (m, 1H),4.16-4.22 (m, 2H), 3.80-3.86 (m, 1H), 3.04-3.08 (m, 2H), 2.78-2.84 (m,1H), 2.48-2.54 (m, 2H), 1.6-2.2 (m, 24H); LC/MS (98.7%, t_(r)=5.612min): m/z=424.6 [M+H]⁺.

In a manner similar to Example 21, Substituted-Quinoxaline-TypePiperidine Compound 402 was prepared by usingSubstituted-Quinoxaline-Type Piperidine Compound 241 in place ofSubstituted-Quinoxaline-Type Piperidine Compound 74 and (S)-(+)-methyl2-amino-2-phenylacetate hydrochloride in place of 4-methoxyaniline(yield 60%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 402,(5)-methyl2-(4-((endo)-9-cyclooctyl-9-azabicyclo[3.3.1]nonan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)-2-phenylacetate,was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 402: LC/MS: m/z=571[M+H]⁺ (Calc: 570).

Substituted-Quinoxaline-Type Piperidine Compound 300 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 402 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 81%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 300,(S)-2-(4-((endo)-9-cyclooctyl-9-azabicyclo[3.3.1]nonan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)-2-phenylaceticacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 300: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 9.56 (d, 1H, J=7.0 Hz), 8.35 (s, 1H), 7.89 (d, 1H, J=7.8Hz), 7.70-7.74 (m, 1H), 7.31-7.51 (m, 7H), 5.84 (s, 1H), 5.52 (d, 1H,J=7.0 Hz) 4.02 (s, 2H), 1.29-3.58 (m, 25H); LC/MS: m/z=557 [M+H]⁺ (Calc:556).

5.36 Example 36

In a manner similar to Example 35, the followingSubstituted-Quinoxaline-Type Piperidine Compounds were prepared from thecompound of formula LB.

Substituted-Quinoxaline-Type Piperidine Compound 262 (yield 19% forthree steps) and the hydrochloride of Substituted-Quinoxaline-TypePiperidine Compound 263 (yield 90%) were prepared by using3-noradamantamine hydrochloride (Sigma-Aldrich) in place of the compoundof formula ED.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 262,endo-4-(9-(hexahydro-2,5-methano-pentalen-3a-yl)-9-aza-bicyclo[3.3.1]non-3-yl)-3-oxo-3,4-dihydro-quinoxaline-2-carboxylicacid ethyl ester, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 262: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.93 (1H, d, J=8 Hz), 7.63 (1H, t, J=8 Hz), 7.55 (1H, bs),7.36 (1H, t, J=8 Hz), 4.52 (2H, q, J=8.5 Hz), 3.55 (2H, m), 2.73-2.38(3H, m), 2.32 (2H, s), 2.22 (1H, t, J=8 Hz), 2.03-1.50 (18H, m), 1.46(3H, t, J=8 Hz). 1.36 (2H, m); LC/MS: m/z=462.6 [M+H]⁺.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 263,4-(9-(hexahydro-2,5-methano-pentalen-3a-yl)-9-aza-bicyclo[3.3.1]non-3-yl)-3-oxo-3,4-dihydro-quinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 263: ¹H NMR: δ_(H) (600MHz, (CD₃)₂SO): 14.05 (1H, bs), 7.91 (1H, bd), 7.80 (1H, bt), 7.69 (1H,bs), 7.48 (1H, bt), 4.85 (1H, bs), 3.55 (2H, m), 2.50-2.20 (6H, m),2.12-1.52 (15H, m), 1.36 (2H, m); LC/MS (100%): m/z=434.2 [M+H]⁺.

In a manner similar to Example 35, the followingSubstituted-Quinoxaline-Type Piperidine Compounds were prepared from thecompound of formula LB except that KOH replaced NaOH in thede-esterification step.

Substituted-Quinoxaline-Type Piperidine Compound 390 and thehydrochloride of Substituted-Quinoxaline-Type Piperidine Compound 333were prepared by using 1-adamantylamine in place of the compound offormula ED.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 390,endo-4-(9-adamantan-1-yl)-9-aza-bicyclo[3.3.1]non-3-yl)-3-oxo-3,4-dihydro-quinoxaline-2-carboxylicacid ethyl ester, was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 390: LC/MS (96.1%,t_(r)=2.374 min): m/z=476.6 [M+H]⁺ (Calc: 475.6).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 333,endo-4-(9-adamantan-1-yl)-9-aza-bicyclo[3.3.1]non-3-yl)-3-oxo-3,4-dihydro-quinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 333: ¹H NMR: δ_(H) (400MHz, CDCl₃): 14.19 (1H, s), 9.21 (1H, m), 8.98 (1H, s), 8.21 (1H, m),7.99 (1H, m), 7.59 (1H, m), 7.01 (1H, m), 4.31 (2H, s), 3.06 (1H, m),2.79 (4H, m), 2.57 (6H, s), 2.31 (5H, m), 1.81 (9H, m); LC/MS (100%,t_(r)=5.604 min): m/z=448.5 [M+H]⁺ (Calc: 447.6).

Substituted-Quinoxaline-Type Piperidine Compound 391 (yield 9.1% forthree steps) and the hydrochloride of Substituted-Quinoxaline-TypePiperidine Compound 333 (yield 38%) were prepared by using thehydrochloride of memantine (Sigma-Aldrich) in place of the compound offormula ED.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 391,endo-4-[9-(3,5-dimethyl-adamantan-1-yl)-9-aza-bicyclo[3.3.1]non-3-yl]-3-oxo-3,4-dihydro-quinoxaline-2-carboxylicacid ethyl ester, was confirmed using LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 391: LC/MS (92.7%,t_(r)=2.453 min): m/z=504.2 [M+H]⁺ (Calc: 503.7).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 334,endo-4-[9-(3,5-dimethyl-adamantan-1-yl)-9-aza-bicyclo[3.3.1]non-3-yl]-3-oxo-3,4-dihydro-quinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 334: ¹H NMR: δ_(H) (400MHz, CDCl₃): 14.09 (1H, s), 9.20 (1H, m), 9.08 (1H, s), 8.21 (1H, m),8.00 (1H, m), 7.59 (1H, m), 7.01 (1H, m), 4.28 (2H, s), 3.17 (1H, m),2.78 (4H, m), 2.39 (3H, s), 2.28 (2H, m), 2.20 (4H, s), 1.80 (3H, m),1.60 (1H, s), 1.51 (2H, m), 1.18-1.45 (5H, m), 0.98 (3H, s); LC/MS(100%, t_(r)=7.12 min): m/z=476.5 [M+H]⁺ (Calc: 475.6).

In a manner similar to Example 35, the followingSubstituted-Quinoxaline-Type Piperidine Compounds were prepared from thecompound of formula LB except that the final HCl treatment was omitted.

Substituted-Quinoxaline-Type Piperidine Compounds 285 (yield 0.42% forthree steps) and 286 (yield 92%) were prepared by using2,4,4-trimethylpentan-2-amine (Sigma-Aldrich) in place of the compoundof formula ED.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 285,ethyl3-oxo-4-((endo)-9-(2,4,4-trimethylpentan-2-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 285: ¹H NMR: δ_(H)(CDCl₃): 7.92 (1H, d, J=7.6 Hz), 7.60 (2H, m), 7.35 (1H, t, J=7.6 Hz),4.80 (1H, m), 4.51 (2H, q, J=7.2 Hz), 3.71 (2H, m), 2.58 (3H, m), 1.94(2H, m), 1.70 (3H, m), 1.57 (3H, s), 1.45 (3H, t, J=7.2 Hz), 1.32 (2H,m), 1.31 (6H, s), 1.04 (9H, s); LC/MS: m/z=454 [M+H]⁺ (Calc: 453.6).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 286,3-oxo-4-((endo)-9-(2,4,4-trimethylpentan-2-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 286: ¹H NMR: δ_(H)(DMSO-d₆): 7.87 (1H, d, J=7.6 Hz), 7.74 (1H, t, J=7.6 Hz), 7.62 (1H,br), 7.44 (1H, t, J=7.6 Hz), 4.80 (1H, br), 3.68 (2H, m), 2.40 (3H, m),1.95 (2H, m), 1.65 (3H, m), 1.55 (2H, s), 1.27 (6H, s), 1.25 (2H, m),1.05 (9H, s); LC/MS (98%, t_(r)=2.09 min): m/z=426 [M+H]⁺ (Calc: 425.6).

Substituted-Quinoxaline-Type Piperidine Compounds 287 and 288 wereprepared by using cyclodecanamine (Sigma-Aldrich) in place of thecompound of formula ED.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 287,ethyl4-((endo)-9-cyclodecyl-9-azabicyclo[3.3.1]nonan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 287: ¹H NMR: δ_(H)(CDCl₃): 7.93 (1H, d, J=8.0 Hz), 7.66-7.52 (2H, m), 7.36 (1H, m), 5.11(1H, br), 4.51 (2H, q, J=7.2 Hz), 3.51 (2H, d, J=11.15 Hz), 3.05 (1H,m), 2.71 (2H, m), 2.39 (1H, m), 2.01 (2H, m), 1.82-1.40 (29H, m), 1.15(2H, m); LC/MS: m/z=480 [M+H]⁺ (Calc: 479.6).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 288,4-((endo)-9-cyclodecyl-9-azabicyclo[3.3.1]nonan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 288: ¹H NMR: δ_(H)(CDCl₃, DCl): 8.70 (0.2H, m), 8.17 (0.8H, m), 7.93 (1H, m), 7.69 (1H,m), 7.29 (1H, m), 6.10 (1H, br), 4.18 (2H, m), 3.60 (2H, br), 3.05 (2H,m), 2.89 (1H, m), 2.60 (2H, m), 2.20 (4H, m), 1.90-1.40 (18H, m); LC/MS(100%, t_(r)=1.87 min): m/z=452 [M+H]⁺ (Calc: 454.6).

Substituted-Quinoxaline-Type Piperidine Compounds 289 and 290 wereprepared by using cyclononanamine (Sigma-Aldrich) in place of thecompound of formula ED.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 289,ethyl4-((endo)-9-cyclononyl-9-azabicyclo[3.3.1]nonan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 289: ¹H NMR: δ_(H)(CDCl₃): 7.93 (1H, d, J=8.11 Hz), 7.63 (2H, m), 7.36 (1H, t, J=8.11 Hz),5.18 (1H, br), 4.51 (2H, q, J=7.1 Hz), 3.51 (2H, d, J=10.65 Hz), 3.04(1H, m), 2.73 (2H, m), 2.40 (1H, m), 2.00 (2H, m), 1.82-1.43 (22H, m),1.14 (2H, m); LC/MS: m/z=466 [M+H]⁺ (Calc: 465.6).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 290,4-((endo)-9-cyclononyl-9-azabicyclo[3.3.1]nonan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 290: ¹H NMR: δ_(H)(CDCl₃): 8.11 (1H, m), 7.87 (1H, d, J=8.11 Hz), 7.57 (1H, m), 7.25 (1H,m), 6.03 (1H, br), 4.16 (2H, s), 3.69 (1H, s), 3.08-2.89 (3H, m), 2.57(2H, m), 2.23-1.38 (21H, m); LC/MS (100%, t_(r)=1.67 min): m/z=438[M+H]⁺ (Calc: 437.6).

Substituted-Quinoxaline-Type Piperidine Compounds 291 and 292 wereprepared by using exo)-bicyclo[3.3.1]nonan-9-amine (Sigma-Aldrich) inplace of the compound of formula ED.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 291,ethyl4-((endo)-9-((exo)-bicyclo[3.3.1]nonan-9-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 291: ¹H NMR: δ_(H)(CDCl₃): 7.93 (1H, d, J=8.11 Hz), m), 7.36 (1.1H, t, J=7.35 Hz), 5.28(1H, m), 4.51 (2H, q, J=7.1 Hz), 3.55 (2H, m), 2.81 (3H, m), 2.36 (1H,m), 2.09-1.41 (22H, m), 1.07 (2H, d, J=12.67 Hz); LC/MS: m/z=464 [M+H]⁺(Calc: 463.6).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 292,4-((endo)-9-((exo)-bicyclo[3.3.1]nonan-9-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 292: ¹H NMR: δ_(H)(CDCl₃): 8.26 (1H, d, J=8.11 Hz), 7.81 (1H, t, J=7.6 Hz), 7.70 (1H, m),7.55 (1H, m), 5.40 (1H, m), 3.61 (2H, d, J=10.14 Hz), 2.85 (1H, s), 2.81(2H, m), 2.35 (1H, m), 2.13-1.46 (19H, m), 1.12 (2H, m); LC/MS (100%,t_(r)=1.67 min): m/z=436 [M+H]⁺ (Calc: 435.6).

5.37 Example 37

In a manner similar to Example 35, the followingSubstituted-Quinoxaline-Type Piperidine Compounds were prepared exceptthat the compound of formula EC was used in place of the compound offormula LB.

Substituted-Quinoxaline-Type Piperidine Compound 242, ethyl4-((endo)-8-cycloheptyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,and the hydrochloride of Substituted-Quinoxaline-Type PiperidineCompound 243 were prepared by using cycloheptanamine (Sigma-Aldrich) inplace of the compound of formula ED.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 243,4-((endo)-8-cycloheptyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 243: ¹H NMR: δ_(H) (400MHz, 1:3 CDCl₃:CD₃OD): 8.01-8.04 (m, 1H), 7.94-7.96 (m, 1H), 7.82-7.86(m, 1H), 7.51-7.55 (m, 1H), 5.7-5.8 (m, 1H), 4.26-4.38 (m, 2H),3.02-3.12 (m, 1H), 2.72-2.85 (m, 2H), 2.20-2.64 (m, 8H), 1.60-1.92 (m,10H); LC/MS (100%, t_(r)=4.981 min): m/z=396.6 [M+H]⁺.

Substituted-Quinoxaline-Type Piperidine Compound 244,endo-4-[8-(3-hydroxy-adamantan-1-yl)-8-aza-bicyclo[3.2.1]oct-3-yl]-3-oxo-3,4-dihydro-quinoxaline-2-carboxylicacid ethyl ester, and the hydrochloride of Substituted-Quinoxaline-TypePiperidine Compound 245 were prepared by using 3-amino-adamantan-1-ol(Sigma-Aldrich) in place of the compound of formula ED.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 245,endo-4-[8-(3-hydroxy-adamantan-1-yl)-8-aza-bicyclo[3.2.1]oct-3-yl]-3-oxo-3,4-dihydro-quinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 245: ¹H NMR: δ_(H) (400MHz, 1:3 CDCl₃:CD₃OD): 8.1 (d, 1H, J=8.8 Hz), 8.02 (dd, 1H, J=1.2, 7.8Hz), 7.83 (ddd, 1H, J=1.5, 7.2, 8.3 Hz), 7.51-7.55 (m, 1H), 6.04-6.18(m, 1H), 4.48-4.52 (m, 2H), 2.94-3.02 (m, 2H), 2.60-3.64 (m, 2H),2.32-2.68 (m, 6H), 2.08-2.24 (m, 6H), 1.6-1.8 (m, 6H); LC/MS (100%,t_(r)=4.338 min): m/z=450.6 [M+H]⁺.

Substituted-Quinoxaline-Type Piperidine Compound 246,endo-4-(8-adamantan-2-yl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-oxo-3,4-dihydro-quinoxaline-2-carboxylicacid ethyl ester (yield 35%), and the hydrochloride ofSubstituted-Quinoxaline-Type Piperidine Compound and 247 (yield 58%)were prepared by using 2-amino-adamantane (Sigma-Aldrich) in place ofthe compound of formula ED.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 247,endo-4-(8-adamantan-2-yl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-oxo-3,4-dihydro-quinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 247: ¹H NMR: δ_(H) (400MHz, 1:3 CDCl₃:CD₃OD): 8.1 (d, 1H, J=8.7 Hz), 8.03 (d, 1H, J=8.1 Hz),7.82-7.86 (m, 1H), 7.51-7.55 (m, 1H), 6.14-6.21 (m, 1H), 4.28-4.42 (m,2H), 3.18-3.26 (m, 1H), 2.97-3.04 (m, 2H), 2.58-2.64 (m, 4H), 2.28-2.44(m, 6H), 1.6-2.2 (m, 10H); LC/MS (97.9%, t_(r)=5.362 min): m/z=434.5[M+H]⁺.

Substituted-Quinoxaline-Type Piperidine Compounds 293 and 294 wereprepared by using cyclodecanamine in place of the compound of formula EDand omitting the final HCl treatment.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 293,ethyl4-((endo)-8-cyclodecyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 293: ¹H NMR: δ_(H)(CDCl₃): 7.91 (1H, m), 7.64-7.54 (2H, m), 7.34 (1H, m), 5.20 (1H, br),4.49 (2H, q, J=7.1 Hz), 3.68 (2H, s), 2.45-2.20 (5H, m), 2.02 (2H, m),1.81 (2H, m), 1.72-1.42 (22H, m); LC/MS: m/z=466 [M+H]⁺ (Calc: 465.6).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 294,4-((endo)-8-cyclodecyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 294: ¹H NMR: δ_(H)(CDCl₃): 7.88 (2H, m), 7.42 (1H, m), 7.24 (1H, m), 5.80 (1H, m), 4.13(2H, m), 3.10 (1H, m), 2.85 (1H, m), 2.60-1.40 (24H, m); LC/MS (99%,t_(r)=1.76 min): m/z=438 [M+H]⁺ (Calc: 437.6).

Substituted-Quinoxaline-Type Piperidine Compounds 295 and 296 wereprepared by using (exo)-bicyclo[3.3.1]nonan-9-amine in place of thecompound of formula ED and omitting the final HCl treatment.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 295,ethyl4-((endo)-8-((exo)-bicyclo[3.3.1]nonan-9-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 295: ¹H NMR: δ_(H)(CDCl₃): 7.92 (1H, d, J=8.11 Hz), 7.62 (1H, t, J=7.86 Hz), 7.52 (1H, d,J=8.62 Hz), 7.35 (1.1H, t, J=7.6 Hz), 5.20 (1H, br), 4.49 (2H, q, J=7.1Hz), 3.68 (2H, s), 2.45-2.20 (5H, m), 2.02 (2H, m), 1.81 (2H, m),1.72-1.42 (24H, m); LC/MS: m/z=450 [M+H]⁺ (Calc: 449.6).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 296,4-((endo)-8-((exo)-bicyclo[3.3.1]nonan-9-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 296: ¹H NMR: δ_(H)(CDCl₃): 8.42 (1H, m), 8.21 (1H, m), 7.92 (1H, m), 7.58 (1H, m), 6.60(1H, m), 4.27 (2H, m), 3.10 (3H, m), 2.60-1.30 (22H, m); LC/MS (100%,t_(r)=1.54 min): m/z=424 [M+H]⁺ (Calc: 423.6).

Substituted-Quinoxaline-Type Piperidine Compounds 297 and 298 wereprepared by using cyclononanamine in place of the compound of formula EDand omitting the final HCl treatment.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 297,ethyl4-((endo)-8-cyclononyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 297: ¹H NMR: δ_(H)(CDCl₃): 7.92 (1H, d, J=8.0 Hz), 7.62 (1H, t, J=8.0 Hz), 7.52 (1H, d,J=8.0 Hz), 7.35 (1H, t, J=8.0 Hz), 5.40 (1H, br), 4.50 (2H, q, J=7.1Hz), 3.68 (2H, s), 2.28-1.40 (26H, m); LC/MS: m/z=450 [M+H]⁺ (Calc:449.6).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 298,4-((endo)-8-cyclononyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 298: ¹H NMR: δ_(H)(CDCl₃): 8.23 (1H, d, J=8.11 Hz), 7.74 (2H, m), 7.53 (1H, t, J=7.6 Hz),5.60 (1H, br), 3.75 (2H, s), 3.49 (1H, s), 2.40-1.47 (22H, m); LC/MS(100%, t_(r)=1.40 min): m/z=422 [M+H]⁺ (Calc: 421.6).

Substituted-Quinoxaline-Type Piperidine Compounds 392 and 365 wereprepared by using pentan-3-amine (Sigma-Aldrich) in place of thecompound of formula ED and omitting the final HCl treatment.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 392,ethyl3-oxo-4-((endo)-8-(pentan-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR.

Substituted-Quinoxaline-Type Piperidine Compound 392: ¹H NMR: δ_(H)(CDCl₃): 0.95 (t, J=7.39 Hz, 6H), 1.40-1.60 (m, 7H), 1.85 (m, 2H), 2.05(m, 2H), 2.15-2.38 (m, 5H), 3.67 (m, 2H), 4.54 (q, J=7.11 Hz, 2H), 5.30(br, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.68 (t, J=8.0Hz, 1H), 7.96 (d, J=8.0 Hz, 1H).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 365,3-oxo-4-((endo)-8-(pentan-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 365: ¹H NMR: δ_(H)(DMSO-d₆): 0.96 (t, J=7.4 Hz, 6H), 1.86 (m, 4H), 2.16-2.27 (m, 6H), 2.66(m, 2H), 2.84 (m, 1H), 4.20 (m, 2H), 6.14 (m, 1H), 7.44 (t, J=8.0 Hz,1H), 7.73 (t, J=8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 8.11 (d, J=8.0 Hz,1H); LC/MS (99%, t_(r)=0.81 min): m/z=370 [M+H]⁺ (Calc: 369.6).

Substituted-Quinoxaline-Type Piperidine Compounds 393 and 356 wereprepared by using cyclododecanamine (Sigma-Aldrich) in place of thecompound of formula ED and omitting the final HCl treatment.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 393,ethyl4-((endo)-8-cyclododecyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 393: ¹H NMR: δ_(H)(CDCl₃): 1.35 (m, 25H), 1.82 (m, 2H), 2.02 (m, 2H), 2.26 (m, 5H), 3.68(m, 2H), 4.49 (q, J=7.1 Hz, 2H), 5.20 (br, 1H), 7.34 (t, J=7.6 Hz, 1H),7.54 (d, J=7.6 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H);LC/MS: m/z=494 [M+H]⁺ (Calc: 493.6).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 356,4-((endo)-8-cyclododecyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 356: ¹H NMR: δ_(H)(CDCl₃): 1.42 (m, 16H), 1.60-2.60 (m, 12H), 2.72 (s, 1H), 3.06 (m, 2H),4.16 (s, 2H), 6.00 (br, 1H), 7.32 (t, J=7.35 Hz, 1H), 7.60 (m, 1H), 7.93(d, J=8.11 Hz, 1H). 8.10 (m, 1H); LC/MS (100%, t_(r)=2.20 min): m/z=466[M+H]⁺ (Calc: 465.6).

Substituted-Quinoxaline-Type Piperidine Compounds 394 and 358 wereprepared by using cycloundecanamine (Sigma-Aldrich) in place of thecompound of formula ED and omitting the final HCl treatment.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 394,ethyl4-((endo)-8-cycloundecyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 394: ¹H NMR: δ_(H)(CDCl₃): 1.30-1.70 (m, 24H), 1.83 (m, 2H), 2.00 (m, 2H), 2.25 (m, 5H),3.66 (m, 2H), 4.50 (d, J=7.14 Hz, 2H), 5.20 (br, 1H), 7.36 (t, J=7.6 Hz,1H), 7.56 (d, J=7.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.91 (d, J=7.6 Hz,1H); LC/MS: m/z=480 [M+H]⁺ (Calc: 479.6).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 358,4-((endo)-8-cycloundecyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 358: ¹H NMR: δ_(H)(CDCl₃): 1.30-1.60 (m, 14H), 1.75 (m, 2H), 2.13 (m, 6H), 2.39 (m, 4H),2.61 (m, 1H), 3.04 (m, 2H), 4.12 (m, 2H), 5.83 (m, 1H), 7.25 (m, 1H),7.44 (m, 1H), 7.85-7.94 (m, 21-1); LC/MS (99%, t_(r)=2.06 min): m/z=452[M+H]⁺ (Calc: 451.6).

5.38 Example 38

The compound of formula MA, 2-(2,2-diethoxyethoxy)-1,1-diethoxyethane,was prepared according the procedure described in C. L. Zirkle et al.,J. Org. Chem. 26:395 (1961). A mixture of the compound of formula MA (25g, 0.14 mmol), AcOH (7 mL), and water (25 mL) was warmed to 100° C. andstirred for 2 h. After cooling to about 25° C., the resulting colorlesssolution was added to 350 mL of a buffer solution containing 36 g ofNa₂HPO₄.7 H₂O and 25 g citric acid. Under an argon atmosphere, 400 mL ofwater and the compounds of formula MB (3-oxopentanedioic acid, 40 g,0.27 mol, Sigma-Aldrich) and MC (phenylmethanamine, 27 g, 0.25 mol) wereadded. After holding the reaction mixture at 26-28° C. for 24 h, it wassaturated with NaCl, neutralized with about 50 g of NaOH to a pH ofabout 11, and extracted four times with DCM (250 mL for eachextraction). The organic portions were combined and concentrated underreduced pressure to provide a brown oil which was diluted with acetone(200 mL), concentrated under reduced pressure, and dried to provideabout 7 g of the compound of formula MD,9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one, as white solid. In amanner similar to Example 18, the benzyl group of the compound offormula MD was removed to provide 3.8 g of the hydrochloride of thecompound of formula ME, 3-oxa-9-azabicyclo[3.3.1]nonan-7-one, as a whitesolid.

In a manner similar to Example 32, the compound of formula MG,9-((Z)-cyclooct-2-enyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one, wasprepared from the compound of formula MF except that the compound offormula ME was used in place of the compound of formula JC (yield 90%).Under a hydrogen atmosphere, a mixture of the compound of formula MG, 5%palladium on carbon (1.0 g, Sigma-Aldrich), and EtOH (20 mL) was stirredat a temperature of about 25° C. for 4 h. After the Pd/C was filteredoff, the filtrate was concentrated under reduced pressure to provide thecompound of formula MH,9-cyclooctyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one.

In a manner similar to Example 1, a mixture of the endo and exo isomersof the compound of formula MI,N¹-9-cyclooctyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)benzene-1,2-diamine,was prepared except that the compound of formula MH was used in place ofthe compound of formula AA. Substituted-Quinoxaline-Type PiperidineCompound 248 was prepared from diethyl 2-oxomalonate in a manner similarto Example 12 except that the compound of formula MI was used in placeof the compound of formula AB (yield 15% from MH).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 248,ethyl4-((endo)-9-cyclooctyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 248: ¹H NMR: δ_(H) (400MHz, CDCl₃): 8.30 (br, 1H), 7.95 (dd, 11-1, J=1.5, 8.1 Hz), 7.64 (ddd,1H, J=1.5, 7.2, 8.2 Hz), 7.35 (ddd, 1H, J=1.1, 7.1, 8.3 Hz), 6.05 (br,1H), 4.52 (t, 2H, J=7.2 Hz), 3.80-3.83 (m, 2H), 3.66-3.71 (m, 2H),3.30-3.34 (m, 2H), 3.04-3.08 (m, 1H), 2.20-2.24 (m, 2H), 1.4-1.8 (m,19H); LC/MS (100%, t_(r)=6.056 min): m/z=454.6 [M+H]⁺ (Calc: 453.6).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound249 was prepared from Substituted-Quinoxaline-Type Piperidine Compound248 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield78%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 249,4-((endo)-9-cyclooctyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 249: ¹H NMR: δ_(H) (400MHz, 1:3 CDCl₃:CD₃OD): 8.25-8.42 (m, 1H), 8.02-8.06 (m, 1H), 7.83-7.86(m, 1H), 7.53 (dd, 1H, J=7.4, 7.9 Hz), 6.24 (br, 1H), 3.80-4.32 (m, 7H),3.20-3.26 (m, 1H), 2.60-3.78 (m, 3H), 1.60-2.24 (m, 14H); LC/MS (99.1%,t_(r)=2.067 min): m/z=426.5 [M+H]⁺.

5.39 Example 39

A reaction mixture of 2-bromo-1,1-diethoxyethane (NA, 25 g,Sigma-Aldrich), 2,2-diethoxy-N-methylethanamine (NB, 1.0 eq,Sigma-Aldrich), TEA (1.0 eq), and K₂CO₃ (1.0 eq) in CH₃CN (200 mL) waswarmed to 60° C. and stirred for 20 h. After cooling to about 25° C.,the reaction mixture was diluted with water, extracted with Et₂O,concentrated under reduced pressure, and distilled (at 56-60° C. and 0.5mmHg) to provide 30 g of the compound of formula NC,3,5-diethoxy-1-methylpiperidine, as a colorless oil (yield 87%). Thecompound of formula NC was treated with 1N HCl (150 mL) at a temperatureof 100° C. for 2 h to provide the compound of formula ND,1-methylpiperidine-3,5-diol. Thereafter, the compound of formula NE,9-benzyl-3-methyl-3,9-diazabicyclo[3.3.1]nonan-7-one, was prepared in amanner similar to the preparation of the compound of formula MD inExample 38 except that the compound of formula ND was used in place ofthe compound of formula MA.

In a manner similar to Example 38, Substituted-Quinoxaline-TypePiperidine Compound 250, ethyl4-((endo)-9-cyclooctyl-3-methyl-3,9-diazabicyclo[3.3.1]nonan-7-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was prepared except that the compound of formula NE was used in place ofthe compound of formula MD.

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound251 was prepared from Substituted-Quinoxaline-Type Piperidine Compound250 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield36%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 251,4-((endo)-9-cyclooctyl-3-methyl-3,9-diazabicyclo[3.3.1]nonan-7-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 251: ¹H NMR: δ_(H) (400MHz, 1:3 CDCl₃:CD₃OD): 8.08-8.11 (m, 1H), 7.86-7.93 (m, 2H), 7.59-7.63(m, 1H), 5.64 (br, 1H), 4.08 (br, 2H), 3.44-3.60 (m, 4H), 3.16 (s, 3H,Nme), 2.66-2.78 (m, 3H), 1.6-2.24 (m, 1614); LC/MS (99.1%, t_(r)=4.586min): m/z=439.2 [M+H]⁺ (Calc: 438.6).

5.40 Example 40

At a temperature of about 25° C., a 28% aqueous ammonia solution wasadded to a mixture of the compound of formula JC (1.0 g, 3.52 mmol) andCHCl₃ (30 mL) and the reaction mixture was stirred for 10 min. Themixture was extracted three times with CHCl₃:H₂O (30 mL for eachextraction), dried (MgSO₄), and concentrated under reduced pressure toprovide a yellow oil. Under a nitrogen atmosphere, to a mixture of theresulting oil and MeOH (300 mL) at a temperature of about 25° C. wasadded 4-isopropylcyclohexanone (0.593 g, 4.23 mmol, Sigma-Aldrich),NaBH₃CN (1.107 g, 17.62 mmol, Sigma-Aldrich) and zinc chloride (4.804 g,35.2 mmol, Sigma-Aldrich). The resulting reaction mixture was stirred ata temperature of about 25° C. for 72 h. Thereafter, the mixture wasconcentrated under reduced pressure, neutralized with 28% aqueousammonia to adjust the pH to about 14, and extracted twice with CHCl₃:H₂O(100 mL for each extraction). The organic portions were combined, dried(MgSO₄), and concentrated under reduced pressure to provide a yellowoil. The oil was chromatographed with an amino-silica gel column(Yamazen Corp. W091-01) eluted with a gradient of from 5%:95%EtOAc:n-hexane to 15%:85% EtOAc:n-hexane to 50%:50% EtOAc:n-hexane toprovide 320 mg of the compound of formula OA (yield 24%) and 989 mg ofthe compound of formula OB (yield 75%), each as a yellow solid.

The identity of the compound of formula OA,(endo)-8-((trans)-4-isopropylcyclohexyl)-N-(2-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-amine,was confirmed using ¹H NMR and LC/MS.

Compound OA: ¹H NMR: δ_(H)(400 MHz, CDCl₃): 8.73 (1H, d, J=6.08 Hz),8.18 (1H, t, J=4.31 Hz), 7.40 (1H, dd, J=8.36, 7.35 Hz), 6.71 (1H, d,J=9.12 Hz), 6.61 (1H, dd, J=8.36, 7.35 Hz), 3.86 (1H, q, J=6.59 Hz),3.56 (2H, s), 2.27 (3H, dd, J=8.36, 4.31 Hz), 2.02-1.94 (6.3H, m), 1.70(6H, m), 1.44-1.40 (1H, m), 1.07 (5H, m), 0.85 (6H, dd, J=11.66, 7.10Hz); LC/MS: m/z=372 [M+H]⁺ (Calc: 371).

The identity of the compound of formula OB,(endo)-8-((cis)-4-isopropylcyclohexyl)-N-(2-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-amine,was confirmed using ¹H NMR and LC/MS.

Compound OB: ¹H NMR: δ_(H)(400 MHz, CDCl₃): 8.74 (1H, d, J=6.08 Hz),8.18 (1H, d, J=8.62 Hz), 7.40 (1H, dd, J=8.11, 7.10 Hz), 6.72 (1H, d,J=8.62 Hz), 6.60 (1H, dd, J=8.36, 7.35 Hz), 3.85 (1H, q, J=6.42 Hz),3.47 (2H, s), 2.52 (1H, s), 2.25 (2H, m), 1.95 (5H, m), 1.75-1.02(17.6H, m), 0.87 (7H, dd, J=5.58, 4.56 Hz); LC/MS: m/z=372 [M+H]⁺ (Calc:371).

In a manner similar to the preparation of the compound of formula CC inExample 6, the compound of formula OC was prepared except that thecompound of formula OB was used in place of the compound of formula CB(yield 98%).

The identity of the compound of formula OC,N¹-((endo)-8-((cis)-4-isopropylcyclohexyl)-8-azabicyclo[3.2.1]octan-3-yl)benzene-1,2-diamine,was confirmed using LC/MS.

Compound OC: LC/MS: m/z=342 [M+H]⁺ (Calc: 341).

In a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 70 in Example 12, Substituted-Quinoxaline-TypePiperidine Compound 252 was prepared except that the compound of formulaOC was used in place of the compound of formula AB (yield 19%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 252,ethyl4-((endo)-8-((cis)-4-isopropylcyclohexyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 252: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.89 (1H, d, J=8.11 Hz), 7.73 (1H, t, J=7.86 Hz), 7.58(1H, d, J=8.62 Hz), 7.44 (1H, t, J=7.6 Hz), 5.20 (1H, br), 4.37 (2H, q,J=7.1 Hz), 3.61 (2H, br), 2.34-1.16 (30H, m), 0.92 (7H, d, J=6.59 Hz);LC/MS: m/z=452 [M+H]⁺ (Calc: 451).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound253 was prepared from Substituted-Quinoxaline-Type Piperidine Compound252 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield64%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 253,4-((endo)-8-((cis)-4-isopropylcyclohexyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 253: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 10.30 (0.8H, s), 9.73 (0.2H, s), 8.12 (1H, d, J=8.62 Hz),7.89 (1H, d, J=7.6 Hz), 7.75 (1H, t, J=7.86 Hz), 7.47 (1H, t, J=7.35Hz), 6.00 (0.8H, t, J=9.63 Hz), 5.24 (0.2H, s), 4.22 (2H, m), 2.91 (1H,m), 2.65 (2H, m), 2.34-2.09 (6H, m), 1.90-1.60 (8H, m), 1.37-1.14 (3H,m), 0.90 (6H, d, J=6.08 Hz); LC/MS (100%, t_(r)=1.66 min): m/z=424[M+H]⁺ (Calc: 423).

In a manner similar to the above preparation ofSubstituted-Quinoxaline-Type Piperidine Compounds 252 and 253, thefollowing Substituted-Quinoxaline-Type Piperidine Compounds wereprepared except that the compound of formula OA was used in place offrom the compound of formula OB.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 254,ethyl4-((endo)-8-((trans)-4-isopropylcyclohexyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 254: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.88 (1H, d, J=7.6 Hz), 7.77 (1H, t, J=7.1 Hz), 7.65 (1H,d, J=6.59 Hz), 7.44 (1H, t, J=7.35 Hz), 5.17 (1H, br), 4.36 (2H, t,J=7.1 Hz), 3.69 (2H, d, J=16.22 Hz), 2.23 (2H, q, J=9.97 Hz), 2.02-1.71(14H, m), 1.41-1.30 (5H, m), 1.08-0.84 (15H, m); LC/MS: m/z=452 [M+H]⁺(Calc: 451).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 255,4-((endo)-8-((trans)-4-isopropylcyclohexyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 255: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 10.22 (0.8H, s), 9.72 (0.2H, s), 8.09 (1H, d, J=8.62 Hz),7.89 (1H, d, J=8.11 Hz), 7.76 (1H, t, J=7.86 Hz), 7.47 (1H, t, J=7.6Hz), 5.97 (0.8H, t, J=9.38 Hz), 5.23 (0.2H, s), 4.31 (1.5H, s), 4.13(0.511, s), 2.83 (1H, s), 2.63-2.55 (2H, m), 2.24 (8H, tt, J=30.92, 8.28Hz), 1.95-1.22 (7H, m), 1.04 (3H, s), 0.86 (6H, d, J=6.59 Hz); LC/MS(98%, t_(r)=1.77 min): m/z=424 [M+H]⁺ (Calc: 423).

In a manner similar to the above preparation ofSubstituted-Quinoxaline-Type Piperidine Compounds 252 and 253, thefollowing Substituted-Quinoxaline-Type Piperidine Compounds wereprepared except that 4-tert-butylcyclohexanone (Sigma-Aldrich) was usedin place of 4-iso-propylcyclohexanone and titanium(IV) iso-propoxide(Sigma-Aldrich) was used in place of zinc chloride.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 256,ethyl4-((endo)-8-((cis)-4-tert-butylcyclohexyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 256: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.89 (1H, d, J=8.11 Hz), 7.69 (1H, t, J=7.6 Hz), 7.54(1H, d, J=8.62 Hz), 7.44 (1H, t, J=7.6 Hz), 5.22 (1H, s), 4.37 (2H, q,J=7.1 Hz), 3.62 (2H, s), 2.36 (1H, s), 2.19 (4H, m), 1.93 (4H, m), 1.62(4H, m), 1.36 (8H, m), 1.09 (1H, m), 0.94 (9H, d, J=19.77 Hz); LC/MS:m/z=466 [M+H]⁺ (Calc: 465).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 257,4-((endo)-8-((cis)-4-tert-butylcyclohexyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 257: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 10.06 (0.7H, br), 8.85 (0.311, s), 8.13 (1H, d, J=9.12Hz), 7.89 (1H, d, J=8.11 Hz), 7.75 (1H, t, J=7.35 Hz), 7.47 (1H, t,J=7.1 Hz), 6.17 (0.7H, br), 5.26 (0.3H, s), 4.22 (2H, s), 3.63 (0.3H,br), 3.04 (0.7H, br), 2.69 (2H, dd, J=20.53, 11.41 Hz), 2.41-1.50 (15H,m), 1.17 (1H, m), 0.90-0.82 (9H, m); LC/MS (100%, t_(r)=1.87 min):m/z=438 [M+H]⁺ (Calc: 437).

In a manner similar to the above preparation ofSubstituted-Quinoxaline-Type Piperidine Compounds 256 and 257, thefollowing Substituted-Quinoxaline-Type Piperidine Compounds wereprepared except that the compound of formula OE was used in place offrom the compound of formula OF.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 258,ethyl4-((endo)-8-((trans)-4-tert-butylcyclohexyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 258: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.88 (1H, d, J=7.6 Hz), 7.76 (1H, d, J=8.11 Hz), 7.66(1H, s), 7.44 (1H, m), 4.37 (2H, q, J=6.93 Hz), 3.69 (2H, m), 2.23 (2H,d, J=12.17 Hz), 1.87 (15H, m), 1.32 (3H, m), 1.02 (6H, m), 0.84 (9H, s);LC/MS: m/z=466 [M+H]⁺ (Calc: 465).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 259,4-((endo)-8-((trans)-4-tert-butylcyclohexyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 259: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 10.22 (0.8H, s), 9.69 (0.2H, s), 8.09 (1H, d, J=8.11 Hz),7.89 (1H, d, J=8.11 Hz), 7.76 (1H, t, J=7.1 Hz), 7.47 (1H, t, J=7.35Hz), 5.96 (0.8H, dd, J=13.18, 5.58 Hz), 5.24 (0.2H, s), 4.23 (2H, m),2.85 (1H, br), 2.58 (2H, br), 2.25 (7H, m), 1.95-1.56 (4H, m), 1.27 (1H,m), 1.11-0.86 (12H, m); LC/MS (100%, t_(r)=1.92 min): m/z=438 [M+H]⁺(Calc: 437).

5.41 Example 41

Substituted-Quinoxaline-Type Piperidine Compound 260 was prepared in amanner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 252 in Example 40 except that 1H-inden-2(3H)-one(Sigma-Aldrich) was used in place of 4-iso-propylcyclohexanone (yield23%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 260,ethyl4-((endo)-8-(2,3-dihydro-1H-inden-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 260: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.88 (1H, d, J=7.6 Hz), 7.74 (2H, d, J=7.1 Hz), 7.44 (1H,t, J=7.6 Hz), 7.15 (4H, dt, J=25.52, 4.31 Hz), 5.23 (1H, br), 4.38 (2H,q, J=7.1 Hz), 3.59 (2H, s), 3.25-3.07 (3H, m), 2.78 (2H, m), 2.33 (2H,dd, J=21.54, 8.87 Hz), 2.05 (4H, dd, J=28.39, 16.73 Hz), 1.76 (2H, d,J=7.1 Hz), 1.32 (3H, t, J=6.84 Hz); LC/MS: m/z=444 [M+H]⁺ (Calc: 443).

The hydrochloride of Substituted-Quinoxaline-Type Piperidine Compound261 was prepared from Substituted-Quinoxaline-Type Piperidine Compound260 in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 174 in Example 7 (yield>98%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 261,4-((endo)-8-(2,3-dihydro-1H-inden-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 261: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 11.42 (0.7H, s), 10.78 (0.2H, s), 8.09 (1H, d, J=8.11Hz), 7.90 (1H, d, J=7.6 Hz), 7.76 (1H, t, J=7.1 Hz), 7.47 (1H, t, J=7.6Hz), 7.25 (4H, d, J=13.18 Hz), 6.04-6.00 (0.8H, m), 5.32 (0.2H, s), 4.11(3H, m), 3.58 (2H, m), 2.76-2.68 (2H, m), 2.55-2.20 (11H, m); LC/MS(100%, t_(r)=1.2 min): m/z=416 [M+H]⁺ (Calc: 415).

5.42 Example 42

To a solution of the compound of formula QA((exo)-bicyclo[3.3.1]nonan-3-amine, 10.44 mmol) in EtOH (3.1 mL) andwater (0.7 mL), K₂CO₃ (144 mg, 1.04 mmol), at a temperature of about 25°C. was added a mixture of the compound of formula LB (4060 mg, 12.53mmol) in EtOH (29 mL), and water (18 mL). After the addition, theresulting reaction mixture was warmed to a temperature of 90° C. andstirred for 5 h. Thereafter, the reaction mixture was cooled to atemperature of about 0° C. to provide a white precipitate. Theprecipitate was filtrated, washed twice with water (8 mL for each wash),and dried to provide 1580 mg of the compound of formula QB as a whitesolid (yield 57.9%).

The identity of the compound of formula QB,9-((exo)-bicyclo[3.3.1]nonan-3-yl)-9-azabicyclo[3.3.1]nonan-3-one, wasconfirmed using ¹H NMR and LC/MS.

Compound QB: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 1.40-1.70 (m, 12H),1.75-1.90 (m, 2H), 1.90-2.10 (m, 4H), 2.20 (d, J=0.20 Hz, 2H), 2.60 (m,2H), 3.35 (m, 1H), 3.66 (m, 2H); LC/MS: m/z=262.1 [M+1]⁺ (Calc: 261).

Under a nitrogen atmosphere, to a solution of the compound of formula QB(1020 mg, 3.90 mmol) in CH₂Cl₂ (15 mL) at a temperature of about 25° C.was added 1,2-phenylenediamine (1266 mg, 11.71 mmol) and 2-ethylhexanoicacid (0.938 mL, 5.85 mmol). The mixture was stirred at a temperature ofabout 25° C. for 30 min to provide reaction mixture 1.

Under a nitrogen atmosphere, to a solution of sodium tetrahydroborate(590 mg, 15.61 mmol) in CH₂Cl₂ (10 mL) at a temperature of about 25° C.was added 2-ethylhexanoic acid (8.75 mL, 54.6 mmol). The mixture wasstirred at a temperature of about 25° C. for 30 min to provide reactionmixture 2.

Under a nitrogen atmosphere, to reaction mixture 1 at 0° C. was addedreaction mixture 2 dropwise over a 15 min period. After the addition,the resulting reaction mixture was warmed to a temperature of about 25°C. and stirred for 30 min. Thereafter, the reaction mixture was warmedto a temperature of 60° C. and stirred for 16 h. After cooling thereaction mixture to a temperature of about 25° C., saturated aqueousNaHCO₃ (20 mL) was added, the mixture stirred for 10 min, then extractedtwice with 1M aqueous K₂CO₃/EtOAc (200 mL for each extraction). Theorganic portions were combined, dried (Na₂SO₄), and concentrated underreduced pressure to provide a brown solid. The solid was chromatographedwith an amino-silica gel column (Yamazen Corp. W091-01) eluted with agradient of from 0%:100% EtOAc:n-hexane to 30%:70% EtOAc:n-hexane toprovide 815 mg of the compound of formula Q as a colorless solid (yield59%).

The identity of the compound of formula QC,N¹-((endo)-9-((exo)-bicyclo[3.3.1]nonan-3-yl)-9-azabicyclo[3.3.1]nonan-3-yl)benzene-1,2-diamine,was confirmed using ¹H NMR and LC/MS.

Compound QC: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 1.02-1.83 (m, 17H), 2.01(m, 5H), 2.40-2.48 (m, 2H), 3.06-3.45 (m, 6H), 3.76 (br, 1H), 6.61-6.82(m, 4H); LC/MS: m/z=354.1 [M+H]⁺ (Calc: 353).

Under a nitrogen atmosphere, to a solution of the compound of formula QC(815 mg, 2.305 mmol) in toluene (16 mL) at a temperature of about 25° C.was added diethyl 2-oxomalonate (0.407 mL, 2.54 mmol) and AcOH (0.145mL, 2.54 mmol). After the addition, the resulting reaction mixture waswarmed to a temperature of 130° C. and stirred for 1 h. Thereafter, thereaction mixture was cooled to a temperature of about 25° C. andconcentrated under reduced pressure to provide a sticky oil. The oil wasdiluted with saturated aqueous NaHCO₃, extracted twice with CHCl₃/water(100 mL for each extraction), dried (Na₂SO₄), and concentrated underreduced pressure to provide an orange solid. The solid waschromatographed with an amino-silica gel column (Yamazen Corp. W091-01)eluted with a gradient of from 0%:100% EtOAc:n-hexane to 20%:80%EtOAc:n-hexane to provide 560 mg of Substituted-Quinoxaline-TypePiperidine Compound 395 as a colorless solid (yield 52%).

Alternatively, compound 395 can be prepared as follows:

Under a nitrogen atmosphere, to a solution of the compound of formula QC(11.04 g, 31.2 mmol) in toluene (202 mL) at a temperature of about 25°C. was added diethyl 2-ketomalonate (6.02 mL, 37.5 mmol) and AcOH (2.143mL, 37.5 mmol). After the addition, the resulting reaction mixture waswarmed to a temperature of 130° C. and stirred for 1 h. Thereafter, thereaction mixture was cooled to a temperature of about 25° C. andconcentrated under reduced pressure to provide a sticky oil. The oil wasdiluted with saturated aqueous NaHCO₃, extracted twice with CHCl₃ (600mL for each extraction), dried (Na₂SO₄), and concentrated under reducedpressure to provide an orange solid. The resulting orange solid wassonicated by n-hexane/Et₂O (4/1), collected by filtration and driedunder reduced pressure at 65° C. for 8 hr to give1-(exo-9-bicyclo[3.3.1]-endo-9-aza-bicyclo[3.3.1]non-3-yl)-2-oxo-1,2-dihydro-quinoxaline-3-carboxylicacid ethyl ester 395 as a pale yellow solid. The remaining filtrate waspurified by column chromatography (silica-gel; CHCl₃/MeOH=100/0˜95/5) togive further 395 as a pale yellow solid. (Combined Yield; 9.83 g, 67%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 395,ethyl4-((endo)-9-((exo)-bicyclo[3.3.1]nonan-3-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 395: ¹H NMR: δ_(H) (400MHz, CDCl₃): 1.04-1.11 (m, 2H), 1.35-1.86 (m, 17H), 1.92-2.02 (m, 6H),2.37-2.47 (m, 1H), 2.67-2.79 (m, 1H), 3.46-3.56 (m, 3H), 4.51 (q, J=7.07Hz, 2H), 5.20 (m, 1H), 7.34-7.37 (m, 1H), 7.63 (t, J=6.57 Hz, 2H), 7.92(d, J=8.08 Hz, 1H); LC/MS: m/z=464.2 [M+H]⁺ (Calc: 463).

To a suspension of Substituted-Quinoxaline-Type Piperidine Compound 395(561 mg, 1.21 mmol) in ethanol (15 mL) at a temperature of about 25° C.was added 2N aqueous NaOH (1.812 mL, 3.62 mmol). The resulting reactionmixture was stirred at a temperature of about 25° C. for 1 h.Thereafter, the reaction mixture was concentrated under reduced pressureto provide a residue. The residue was diluted with water (10 mL) to forma colorless solution, neutralized with 2N aqueous HCl (2.3 mL), andsonicated to provide a white precipitate. The precipitate was collectedby filtration, washed with water, and dried for 5 h under reducedpressure at 75° C. to provide 396 mg of Substituted-Quinoxaline-TypePiperidine Compound 362 as a colorless solid (yield 75%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 362,4-((endo)-9-((exo)-bicyclo[3.3.1]nonan-3-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 362: ¹H NMR: δ_(H) (400MHz, CDCl₃): 0.83 (dq, J=8.72, 2.78 Hz, 1H), 1.22 (s, 1H), 1.38 (br,1H), 1.54 (d, J=12.63 Hz, 1H), 1.69 (s, 6H), 1.87 (m, 4H), 2.05 (t,J=13.89 Hz, 2H), 2.22 (s, 2H), 2.51 (dd, J=19.71, 11.12 Hz, 2H), 2.70(m, 3H), 2.98 (t, J=12.38 Hz, 2H), 4.11-4.22 (m, 3H), 6.65 (br, 1H),7.51-7.62 (m, 4H), 7.93 (t, J=7.83 Hz, 1H), 8.16 (d, J=8.08 Hz, 1H),8.96 (dd, J=7.83, 6.32 Hz, 1H), 10.89 (s, 1H); LC/MS (100%, t_(r)=1.55min): m/z=436.2 [M+H]⁺ (Calc: 436).

Alternatively the compound QC and Substituted-Quinoxaline-TypePiperidine Compound 362 can be synthesized via an different route, whichis shown below:

Compound QB′ was prepared as follows:

Under a nitrogen atmosphere, to a suspension of the compound of formulaQB (10.77 g, 41.2 mmol) in ethanol (215 mL) at a temperature of about25° C. was added hydroxylamine hydrochloride (4.29 g, 61.8 mmol) andsodium acetate (5.07 g, 61.8 mmol). After the addition, the mixture wasstirred at this temperature for 1.5 hr. After quenching with water (50mL), the mixture was separated by CHCl₃/saturated NaHCO₃ (200 mL foreach extraction). The organic portions were combined, dried over Na₂SO₄,and concentrated to under reduced pressure to give9-bicyclo[3.3.1]non-3-yl-9-aza-bicyclo[3.3.1]nonan-3-one oxime (QB′) asa pale yellow solid which was used in the next reaction without furtherpurification (Yield; 11.39 g, 100%).

The identity of the compound of formula QB′,9-bicyclo[3.3.1]non-3-yl-9-aza-bicyclo[3.3.1]nonan-3-one oxime, wasconfirmed by LC/MS.

Compound QB′: LC/MS: m/z=277.45 [M+H]⁺ (Calc: 276.42).

Compound QB″ was prepared as follows:

To a solution of QB′, (11.39 g, 41.2 mmol) in AcOH (203 mL) at atemperature of about 25′C was added platinum(IV) oxide (1.871 g, 8.24mmol). The mixture was stirred at a temperature of about 25° C. for 24hr under a hydrogen atmosphere at 5 atm pressure. After filtration andwashing with AcOEt (100 mL), the filtrate was concentrated under reducedpressure to give a sticky yellow oil. To this oil water was added, andthe resulting mixture was neutralized by 28% aqueous ammonia solution togive a white gel like precipitate. The mixture was extracted twice usingCHCl₃/MeOH/H₂O (700 mL for each extraction). The combined organic phaseswere dried over MgSO₄ and concentrated in vacuo to give the desiredproduct,9-exo-bicyclo[3.3.1]non-3-yl-9-endo-aza-bicyclo[3.3.1]non-3-ylamine QB″only in the endo-form, as a colorless solid, which was used in the nextreaction without purification. (Yield; 9.07 g, 84%).

The identity of the compound of formula QB″,9-exo-bicyclo[3.3.1]non-3-yl-9-endo-aza-bicyclo[3.3.1]non-3-ylamine, wasconfirmed using ¹H NMR and LC/MS.

Compound QB″: ¹H-NMR (400 MHz, DMSO-d₆) δ: 0.92-0.99 (m, 4H), 1.23-1.65(m, 16H), 1.98 (m, 7H), 3.12 (s, 1H), 3.28 (s, 2H); LC/MS: m/z=263.15[M+H]⁺ (Calc: 262.43).

Compound QB′″ was prepared as follows:

Under a nitrogen atmosphere, to a solution of QB″ (9.07 g, 34.6 mmol) inDMF (136 mL) at a temperature of about 25° C. was added potassiumcarbonate (7.16 g, 51.8 mmol) and 1-fluoro-2-nitrobenzene (3.65 mL, 34.6mmol). The mixture was stirred at 100° C. for 2 hr. The reaction mixturewas cooled and quenched with ice-water (100 mL) and saturated NaHCO₃ (10mL) to give a yellow precipitate which was collected by filtration. Theprecipitate was subsequently washed twice with water (50 mL each), driedunder reduced pressure at 70° C. for 8 hr to give the desired product(9-bicyclo[3.3.1]non-3-yl-9-aza-bicyclo[3.3.1]non-3-yl-(2-nitro-phenyl)-amineOB′″ as a yellow solid (Yield; 11.98 g, 90%).

The identity of the compound of formula OB′″,(9-bicyclo[3.3.1]non-3-yl-9-aza-bicyclo[3.3.1]non-3-yl-(2-nitro-phenyl)-amine,was confirmed using ¹H NMR and LC/MS.

Compound QB′″: ¹H-NMR (400 MHz, CDCl₃) δ: 0.85-2.02 (m, 26H), 2.45 (m,2H), 3.49 (m, 3H), 4.03 (t, J=3.79 Hz, 1H), 6.58 (t, J=7.58 Hz, 1H),6.93 (d, J=8.08 Hz, 1H), 7.40 (t, J=7.33 Hz, 1H), 8.09 (dd, J=48.50,7.58 Hz, 2H); LC/MS: m/z=384.2 [M+H]⁺ (Calc: 383.53).

Compound QC was prepared as follows:

Under a hydrogen atmosphere, to a suspension of QB′″ (11.98 g, 31.2mmol) in MeOH (240 mL) at a temperature of about 25° C. was added 10%Pd—C (1.330 g, 1.249 mmol), and the mixture was stirred at thistemperature for 1.5 h. After the addition of CHCl₃ (150 mL), the mixturewas filtrated, washed with CHCl₃ and concentrated in vacuo to giveN-(9-bicyclo[3.3.1]non-3-yl-9-aza-bicyclo[3.3.1]non-3-yl)benzene-1,2-diamine(QC) as a pale green solid which was very pure by NMR and therefore usedin the next step without purification (Yield; 11.04 g, 100%).

The identity of the compound of formula QC,N-(9-bicyclo[3.3.1]non-3-yl-9-aza-bicyclo[3.3.1]non-3-yl)benzene-1,2-diamine,was confirmed using ¹H NMR and LC/MS.

Compound QC: ¹H-NMR (400 MHz, CDCl₃) δ: 1.02-1.83 (m, 17H), 2.01 (m,5H), 2.40-2.48 (m, 2H), 3.06-3.45 (m, 6H), 3.76 (br, 1H), 6.61-6.82 (m,4H); LC/MS: m/z=354.14 [M+H]⁺ (Calc: 353).

The compound of formula QA was prepared as follows:

Under a nitrogen atmosphere, to a solution of the compound of formula QD(adamantane-2-one, 60 g, 399 mmol, Sigma-Aldrich) in AcOH (251 mL, 4394mmol) and methanesulfonic acid (182.00 mL, 2803 mmol, Sigma-Aldrich) ata temperature of 20° C. was added sodium azide (29.9 g, 459 mmol)portionwise over 45 min. After the addition, the resulting reactionmixture was stirred for 30 min at a temperature of from 20° C. to 25° C.Thereafter, ice water (1 L) was poured into the reaction mixture toprovide a white precipitate that was collected by filtration, washedwith water (400 mL), and dried for 4 h under reduced pressure at 60° C.to provide 40.78 g of the compound of formula QE as a colorless solid(yield 69%).

The identity of the compound of formula QE,bicyclo[3.3.1]non-6-ene-3-carbonitrile, was confirmed using ¹H NMR.

Compound QE: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 1.53 (d, J=12.67 Hz, 1H),1.72-2.05 (m, 5H), 2.23 (dt, J=17.91, 8.11 Hz, 2H), 2.41-2.50 (m, 2H),2.96 (dd, J=9.63, 4.06 Hz, 1H), 5.85-5.95 (m, 2H).

Under a hydrogen atmosphere, a mixture of the compound of formula QE(5260 mg, 35.7 mmol), 10% palladium on carbon (570 mg, 0.536 mmol), andMeOH (150 mL) was stirred at a temperature of about 25° C. for 4 h.After the Pd/C was filtered off, the mixture was concentrated underreduced pressure to provide a colorless oil. The oil was chromatographedwith a silica gel column eluted with a gradient of from 3%:97%EtOAc:n-hexane to 20%:80% EtOAc:n-hexane to provide 3500 mg of thecompound of formula QF as a colorless solid (yield 66%).

The identity of the compound of formula QF,bicyclo[3.3.1]nonane-3-carbonitrile, was confirmed using ¹H NMR.

Compound at: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 1.22 (m, 1H), 1.38-1.59 (m,8H), 1.72-1.82 (m, 1H), 2.04-2.08 (m, 2H), 2.20-2.28 (m, 2H), 2.60-2.69(m, 1H).

Under a nitrogen atmosphere, to a solution of the compound of formula QF(2530 mg, 16.95 mmol) in 2-methoxyethanol (26.9 mL, 339 mmol) at atemperature of about 25° C. was added KOH (4280 mg, 76 mmol). After theaddition, the resulting reaction mixture was warmed to a temperature of120° C. and stirred for 16 h. Thereafter, the reaction mixture wascooled to a temperature of about 25° C., 2N aqueous HCl was added toadjust the pH within the range of from about 3 to about 4, and a palebrown precipitate formed. The precipitate was collected by filtration,washed with water, and dried for 3 h under reduced pressure at 70° C. toprovide a pale brown solid, which ¹H NMR showed to be a 1:9 mixture ofendo:exo isomers.

Under a nitrogen atmosphere, to a solution of the above endo:exo isomermixture in 2-methoxyethanol (73.5 mL, 932 mmol) at a temperature ofabout 25° C. was added KOH (4756 mg, 85 mmol). After the addition, theresulting reaction mixture was warmed to a temperature of 120° C. andstirred for 16 h. Thereafter, the reaction mixture was cooled to atemperature of about 25° C., 2N aqueous HCl was added to adjust the pHwithin the range of from about 3 to about 4, and a pale brownprecipitate formed. The precipitate was collected by filtration, washedwith water, and dried for 3 h under reduced pressure at 70° C. toprovide 2187 mg of the compound of formula QG as a pale brown solid,with a melting point of 126-128° C. and present only as the exo isomer(yield 77%).

The identity of the compound of formula QG,(exo)-bicyclo[3.3.1]nonane-3-carboxylic acid, was confirmed using ¹HNMR.

Compound QG: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 1.52-1.85 (m, 10H), 1.96(t, J=6.59 Hz, 4H), 3.10-3.19 (m, 1H).

Under a nitrogen atmosphere, to a solution of the compound of formula QG(2680 mg, 15.93 mmol) in toluene (25 mL) at a temperature of about 25°C. was added TEA (2.65 mL, 19.12 mmol) and DPPA (4.51 mL, 19.12 mmol).After the addition, the resulting reaction mixture was warmed to atemperature of 70° C. and stirred for 1 h. Thereafter, the reactionmixture was cooled to a temperature of about 25° C. and concentratedunder reduced pressure to provide a pale yellow oil, which was driedunder reduced pressure at a temperature of about 25° C. To the oil wasadded phenylmethanol (4.77 mL, 45.9 mmol, Sigma-Aldrich). After theaddition, the resulting reaction mixture was warmed to a temperature of90° C. and stirred for 1.5 h. Thereafter, the reaction mixture wascooled to a temperature of about 25° C. and chromatographed with asilica gel column eluted with a gradient of from 2%:98% EtOAc:n-hexaneto 10%:90% EtOAc:n-hexane to provide 4270 mg of the compound of formulaOH as a colorless solid (yield 98%).

The identity of the compound of formula QH, benzyl(exo)-bicyclo[3.3.1]nonan-3-ylcarbamate, was confirmed using ¹H NMR andLC/MS.

Compound QH: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 1.32 (td, J=12.25, 3.71 Hz,2H), 1.44-1.80 (m, 8H), 1.97-2.09 (m, 4H), 4.28-4.46 (m, 2H), 5.08 (s,2H), 7.26-7.35 (m, 5H); LC/MS: m/z=274:2 [M+H]⁺ (Calc: 273).

Under a hydrogen atmosphere, a mixture of the compound of formula QH(4456 mg, 16.30 mmol), 10% palladium on carbon (694 mg, 0.652 mmol), andEtOH (50 mL) was stirred at a temperature of about 25° C. for 3 h. Afterfiltering off the Pd/C and washing with EtOH, the mixture wasconcentrated under reduced pressure to a volume of 20 mL. The ethanolsolution contained 2270 mg (16.30 mmol) of the compound of formula QA.

In a manner similar to that described above,Substituted-Quinoxaline-Type Piperidine Compounds 396 (yield 8% forthree steps) and 369 (yield 91%) were prepared from the compound offormula LB by using (endo)-bicyclo[3.3.1]nonan-3-amine (QI) in place ofthe compound of formula QA.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 396,ethyl4-((endo)-9-((endo)-bicyclo[3.3.1]nonan-3-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 396: ¹H NMR: δ_(H) (400MHz, CDCl₃): 0.98-1.12 (m, 5H), 1.26 (s, 1H), 1.43 (m, 7H), 1.57 (m,1H), 1.75-1.85 (m, 5H), 2.10 (m, 5H), 2.40-2.45 (m, 1H), 2.72 (br, 2H),3.00-3.07 (m, 1H), 3.53 (d, J=10.11 Hz, 2H), 4.51 (q, J=7.07 Hz, 2H),5.20 (br, 1H), 7.36 (t, J=3.54 Hz, 1H), 7.65 (s, 2H), 7.93 (d, J=8.08Hz, 1H); LC/MS: m/z=464.1 [M+H]⁺ (Calc: 463).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 369,4-((endo)-9-((endo)-bicyclo[3.3.1]nonan-3-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 369: ¹H NMR: δ_(H) (400MHz, CDCl₃): 0.84-0.89 (m, 1H), 1.27 (m, 4H), 1.40-1.52 (m, 2H), 1.66(m, 5H), 1.85 (m, 1H), 2.11 (m, 2H), 2.28 (s, 4H), 2.50 (m, 2H), 2.76(m, 1H), 3.00 (t, J=12.63 Hz, 2H), 3.69-3.74 (m, 1H), 4.16 (d, J=10.11Hz, 2H), 6.78 (s, 1H), 7.56 (t, J=7.58 Hz, 1H), 7.93 (t, J=7.83 Hz, 1H),8.19 (d, J=8.08 Hz, 1H), 9.07 (t, J=7.58 Hz, 1H), 11.08 (s, 1H); LC/MS(100%, t_(r)=1.55 min): m/z=436.2 [M+H]⁺ (Calc: 436).

The compound of formula QI was prepared as follows:

Under a nitrogen atmosphere, to a solution of the compound of formula QD(6.0 g, 39.9 mmol) in methanesulfonic acid (33.7 mL, 519 mmol) at atemperature of 20° C. was added sodium azide (2.726 g, 41.9 mmol)portionwise over 2.5 h. After the addition, the resulting reactionmixture was stirred for 3 days at 20° C. Thereafter, ice water (300 mL)was poured into the reaction mixture to provide a white precipitate thatwas collected by filtration, washed with water, and dried for 6 h underreduced pressure at 40° C. to provide 5.63 g of the compound of formulaQJ as a colorless solid with a melting point of 69-72° C. (yield 58%).

The identity of the compound of formula QJ, methanesulfonic acid4-oxo-adamantan-2-yl ester, was confirmed using ¹H NMR.

Compound QJ: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 1.75-2.12 (m, 9H), 2.31 (m,1H), 2.41-2.50 (m, 2H), 2.58 (s, 1H), 2.88 (s, 1H), 3.05 (d, J=6.59 Hz,3H), 4.80 (t, J=3.55 Hz, 1H).

To a solution of the compound of formula QJ (5.63 g, 23.04 mmol) in EtOH(100 mL) at a temperature of about 25° C. was added a KOH (8.469 g, 151mmol) in water (67 mL) solution. After the addition, the resultingreaction mixture was warmed to a temperature of 110° C. and stirred for12 h. Thereafter, the reaction mixture was cooled to a temperature ofabout 25° C., 10% aqueous HCl was added to adjust the pH within therange of from about 3 to about 4, and a colorless precipitate formed.The precipitate was collected by filtration, washed with water,concentrated under reduce pressure, and dried for 8 h under reducedpressure at 50° C. to provide 3.61 g of the compound of formula as acolorless solid with a melting point of 189-192° C. (yield 94%).

The identity of the compound of formula QK,(endo)-bicyclo[3.3.1]non-6-ene-3-carboxylic acid, was confirmed using ¹HNMR.

Compound QK: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 1.64 (m, 4H), 2.07-2.42 (m,6H), 2.58 (t, J=6.32 Hz, 1H), 5.57-5.68 (m, 2H).

In a manner similar to the preparation of the compound of formula QFabove, the compound of formula QL was prepared from the compound offormula OK (yield 99%).

The identity of the compound of formula QL,(endo)-bicyclo[3.3.1]nonane-3-carboxylic acid, was confirmed using ¹HNMR.

Compound QL: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 1.17 (d, J=13.18 Hz, 1H),1.37-1.82 (m, 10H), 2.12 (m, 4H), 2.51-2.60 (m, 1H).

In a manner similar to the preparation of the compound of formula QHabove, the compound of formula QM was prepared from the compound offormula QL (yield 90%).

The identity of the compound of formula QM, benzyl(endo)-bicyclo[3.3.1]nonan-3-ylcarbamate, was confirmed using ¹H NMR andLC/MS.

Compound QM: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 1.31 (m, 2H), 1.44-1.76 (m,9H), 2.04 (s, 2H), 2.09 (s, 2H), 4.31-4.40 (m, 2H), 5.08 (s, 2H),7.28-7.39 (m, 5H); LC/MS: m/z=274.2 [M+H]⁺ (Calc: 273).

Under a hydrogen atmosphere, a mixture of the compound of formula QM(4.11 g, 15.03 mmol), 10% palladium on carbon (0.64 g, 0.601 mmol), andEtOH (45 mL) was stirred at a temperature of about 25° C. for 3 h. Afterfiltering off the Pd/C and washing with EtOH, the mixture wasconcentrated under reduced pressure to a volume of 10 mL. The ethanolsolution contained 2.093 g (15.03 mmol) of the compound of formula QI.

Alternatively the compound of formula QA can be prepared by the twofurther synthetic routes shown below:

The compound of formula QR can be prepared according to a literatureprocedure described in “Improved synthetic methods forbicyclo[3.3.1]nonan-3-one”. Mosose, Takefumi; Muraoka, Osamu; Chemicaland Pharmaceutical Bulletin 26(1):288-295 (1978) (Lit. 11) starting fromcyclohexen-2-one, QP. The compound of formula QE can also be preparedstarting from cis-cyclohexane-1,3-diacetic acid diethyl ester, asdescribed in H. K. Hall, J. Org. Chem. 28:3213-3214 (1963) (Lit. 12).

The compound of formula QU can be prepared as follows (Lit. 12):

Concentrated sulfuric acid (2 mL) was added at a temperature of about25° C. to a solution of phenyl-1,3-diacetic acid (QT, 50 g, 0.26 mol,TCI US) in ethanol (500 mL). The resulting mixture was heated underreflux for 24 h. After cooling to a temperature of about 25° C., themixture was concentrated to about 200 mL under reduced pressure, anddiluted with toluene (400 mL). The toluene solution was washed withwater (100 mL), and brine (100 mL) and concentrated to dryness in vacuoto give intermediate phenyl-1,3-diacetic acid diethyl ester as acolorless oil (63 g, 98%).

The identity of the intermediate phenyl-1,3-diacetic acid diethyl esterwas confirmed using ¹H NMR.

Intermediate phenyl-1,3-diacetic acid diethyl ester: ¹H NMR (CDCl₃, 400MHz): 7.26-7.3 (m, 1H), 7.18-7.21 (m, 3H), 4.15 (q, J=7.1 Hz, 4H), 3.6(s, 4H), 1.25 (t, J=7.2 Hz, 6H).

A mixture of phenyl-1,3-diacetic acid diethyl ester (63 g, 0.25 mol) andplatinum dioxide (2 g, 0.09 mol) in acetic acid (250 mL) was degassedand stirred under an hydrogen atmosphere at 30° C. for 15 h. Thereaction mixture was flushed with argon, and diluted with water (40 mL).Subsequently, the catalyst was removed by filtration and the solutionwas concentrated to about 200 mL. The resulting mixture was then dilutedwith toluene (400 mL). The mixture was washed with water twice (100 mLeach), NaHCO₃ (100 mL each) and brine (100 mL). The solvent was removedunder reduced pressure to give crude cis-cyclohexane-1,3-diacetic aciddiethyl ester QU as a colorless oil (Lit. 12).

The identity of the compound of formula QU was confirmed using ¹H NMR.

Compound QU: ¹H NMR (CDCl₃, 400 MHz): 4.15 (q, J=7.2 Hz, 4H), 2.17 (d,J=7.0 Hz, 4H), 1.4-1.9 (m, 7H), 1.25 (t, J=7.1 Hz, 6H), 0.83-0.92 (m,2H), 0.71 (dd, J=11.8, 11.9 Hz).

The compound of formula QV can be prepared as follows:

Cis-cyclohexane-1,3-diacetic acid diethyl ester QU was dissolved in dryDME (300 mL). To this solution, sodium hydride (15 g) was added and thesuspension stirred at 94° C. for 16 h. After cooling, the reactionmixture was slowly poured into ice-water (500 mL) and extracted fourtimes with EtOAc (200 mL each). The combined organic layer was washedwith brine, and concentrated to give3-oxo-bicyclo[3.3.1]nonane-2-carboxylic acid ethyl ester QV which wasused without purification in the next step.

Alternative preparation of bicyclo[3.3.1]nonan-3-one (QR):

Compound QV from the previous reaction was dissolved in ethanol (150mL). To this solution, sodium hydroxide (30 g, 750 mmol) in water (150mL) was added and the mixture heated to 70° C. for 8 h. The reactionmixture was concentrated in vacuo, diluted with brine (150 mL) andextracted three times with ether (150 mL each). The combined organicextracts were concentrated to dryness in vacuo to givebicyclo[3.3.1]nonan-3-one QR as a white solid (Yield: 18 g, 51% from1,3-phenyl-diacetic acid).

The identity of the compound of formula QR was confirmed using ¹H NMR.

Compound QR: ¹H-NMR (CDCl₃) δ: 2.52-1.31 (m, 6H), 1.82 (m, 2H),1.70-1.56 (m, 5H), 1.54-1.32 (m, 2H).

Preparation of bicyclo[3.3.1]nonan-3-one oxime (QS):

Under a nitrogen atmosphere, to a solution of QR (975 mg, 7.05 mmol) inethanol (40 mL) at a temperature of about 25° C. was added sodiumacetate (1,157 mg, 14.11 mmol) and hydroxylamine hydrochloride (980 mg,14.11 mmol). The mixture was stirred at a temperature of about 25° C.for 2 hr. The reaction mixture was diluted with saturated NaHCO₃, thenextracted thrice with EtOAc (30 mL each). The organic layers werecombined and washed with saturated NaCl. The combined organic layerswere dried over MgSO₄ and evaporated in vacuo to give QS (800 mg, 76%)as a yellow solid. The oxime was used for the next reaction withoutpurification.

The identity of the compound of formula QS was confirmed using ¹H NMR.

Compound QS: ¹H-NMR (CDCl₃) δ: 1.40 (m, 1H), 1.50-1.80 (m, 8H),1.99-2.17 (m, 3H), 2.40 (d, J=8.0 Hz, 2H), 3.20 (d, J=16.0 Hz, 1H).

Alternative preparation of bicyclo[3.3.1]non-3-ylamine (QA) (Ref: J.Med. Chem. 49:1781-1791 (2006)):

Under a nitrogen atmosphere, to a refluxing suspension of sodium (2.401g, 104 mmol) in toluene (20 mL) at a temperature of about 115° C. wasadded dropwise over 30 min bicyclo[3.3.1]nonan-3-one oxime (QS, 1.60 g,10.44 mmol) in 2-propanol (8 mL). The mixture was stirred at reflux for2 hr. After addition of the oxime solution is completed, 2-propanol (3mL) was added dropwise. The reaction mixture was heated to reflux untilall of the Na was consumed followed by cooling to a temperature of about25° C. The reaction mixture was then quenched by the addition of H₂O (20mL). The organic layer was separated, and washed twice with 1N HCl (30mL each). The acidic solution was made alkaline by the addition of 2NNaOH (50 mL), and extracted thrice with Et₂O (50 mL each). The organiclayers were combined and washed with saturated NaCl (50 mL). The organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo to giveof bicyclo[3.3.1]non-3-ylamine QA. This compound was used in the nextstep without purification in 2-propanol solution.

The identity of the compound of formula QA was confirmed using ¹H NMR.

Compound QA: ¹H-NMR (CDCl₃) δ: 1.20-1.70 (m, 10H), 1.90 (m, 4H), 3.38(m, 1H).

5.43 Example 43

To a mixture of the compound of formula QA (2270 mg, 16.30 mmol), K₂CO₃(225.3 mg, 1.63 mmol), EtOH (20 mL), and water (5 mL) at a temperatureof about 25° C. was added dropwise a mixture of the compound of formulaEC (5058 mg, 16.30 mmol), EtOH (20 mL), and water (27 mL). After theaddition, the resulting reaction mixture was warmed to a temperature of90° C. and stirred for 4 h. Thereafter, the reaction mixture was cooledto a temperature of about 25° C., diluted with saturated aqueous NaHCO₃,then extracted twice with EtOAc/water (100 mL for each extraction). Theorganic portions were combined, dried (Na₂SO₄), and concentrated underreduced pressure to provide an oil. The oil was chromatographed with asilica gel column eluted with a gradient of from 20%:80% EtOAc:n-hexaneto 80%:20% EtOAc:n-hexane to provide 2030 mg of the compound of formulaRA as a colorless solid (yield 50%).

The identity of the compound of formula RA,8-((exo)-bicyclo[3.3.1]nonan-3-yl)-8-azabicyclo[3.2.1]octan-3-one, wasconfirmed using ¹H NMR and LC/MS.

Compound RA: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 1.79 (m, 12H), 2.26 (m,8H), 2.87 (d, J=13.64 Hz, 2H), 3.52 (td, J=11.12, 5.56 Hz, 1H), 3.99 (s,2H); LC/MS: m/z=248.5 [M+H]⁺ (Calc: 247).

Under a nitrogen atmosphere, to a solution of the compound of formula RA(2029 mg, 8.20 mmol) in CH₂Cl₂ (25 mL) at a temperature of about 25° C.was added 1,2-phenylenediamine (2661 mg, 24.61 mmol) and 2-ethylhexanoicacid (1.971 mL, 12.30 mmol). The mixture was stirred at a temperature ofabout 25° C. for 30 min to provide reaction mixture 1.

Under a nitrogen atmosphere, to a solution of sodium tetrahydroborate(1241 mg, 32.8 mmol) in CH₂Cl₂ (17 mL) at a temperature of about 25° C.was added 2-ethylhexanoic acid (18.40 mL, 115 mmol). The mixture wasstirred at a temperature of about 25° C. for 30 min to provide reactionmixture 2.

Under a nitrogen atmosphere, to reaction mixture 1 at 0° C. was addedreaction mixture 2 dropwise over a 15 min period. After the addition,the resulting reaction mixture was warmed to a temperature of about 25°C. and stirred for 30 min. Thereafter, the reaction mixture was warmedto a temperature of 60° C. and stirred for 16 h. After cooling thereaction mixture to a temperature of about 25° C., saturated aqueousNaHCO₃ (20 mL) was added, the mixture stirred for 10 min, then extractedtwice with 1M aqueous K₂CO₃/EtOAc (150 mL for each extraction). Theorganic portions were combined, dried (Na₂SO₄), and concentrated underreduced pressure to provide a yellow oil. The oil was chromatographedwith a silica gel column eluted with a gradient of from 97%:3%CHCl₃:(10% NH₃ in MeOH) to 80%:20% CHCl₃:(10% NH₃ in MeOH) to provide874 mg of the compound of formula RB as a pale yellow amorphous solid(yield 31%).

The identity of the compound of formula RB,-((endo)-8-((exo)-bicyclo[3.3.1]nonan-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)benzene-1,2-diamine,was confirmed using ¹H NMR and LC/MS.

Compound RB: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 0.91 (m, 3H), 1.26-2.10 (m,20H), 2.35 (m, 2H), 3.28-3.33 (m, 1H), 3.69 (m, 3H), 6.57 (d, J=7.58 Hz,1H), 6.75 (m, 3H); LC/MS: m/z=340.6 [M+H]⁺ (Calc: 339).

Under a nitrogen atmosphere, to a solution of the compound of formula RB(870 mg, 2.56 mmol) in xylene (15 mL) at a temperature of about 25° C.was added diethyl 2-oxomalonate (0.494 mL, 3.07 mmol) and AcOH (0.176mL, 3.07 mmol). After the addition, the resulting reaction mixture waswarmed to a temperature of 130° C. and stirred for 1 h. Thereafter, thereaction mixture was cooled to a temperature of about 25° C., dilutedwith saturated aqueous NaHCO₃, extracted twice with EtOAc (100 mL foreach extraction), dried (Na₂SO₄), and concentrated under reducedpressure to provide an orange oil. The oil was chromatographed with anamino-silica gel column (Yamazen Corp. W091-01) eluted with a gradientof from 5%:95% EtOAc:n-hexane to 30%:70% EtOAc:n-hexane to provide apale yellow solid. The solid was triturated with 1:4 Et₂O:n-hexane anddried under reduced pressure at 70° C. to provide 343 mg ofSubstituted-Quinoxaline-Type Piperidine Compound 397 as a colorlesssolid (yield 30%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 397,ethyl4-((endo)-8-((exo)-bicyclo[3.3.1]nonan-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 397: ¹H NMR: δ_(H) (400MHz, CDCl₃): 0.83-0.88 (m, 1H), 126 (dd, J=33.09, 17.94 Hz, 3H), 1.51(m, 11H), 1.91 (m, 8H), 2.20 (s, 3H), 2.79 (dt, J=11.62, 3.66 Hz, 1H),3.70 (s, 2H), 4.50 (q, J=7.07 Hz, 2H), 5.20 (br, 1H), 7.34 (t, J=7.07Hz, 1H), 7.61 (q, J=7.92 Hz, 2H), 7.91 (d, J=7.58 Hz, 1H); LC/MS:m/z=450.1 [M+H]⁺ (Calc: 449).

To a solution of Substituted-Quinoxaline-Type Piperidine Compound 397(343 mg, 0.763 mmol) in ethanol (10 mL) at a temperature of about 25° C.was added 2N aqueous NaOH (1.144 mL, 2.289 mmol). The resulting reactionmixture was stirred at a temperature of about 25° C. for 1 h.Thereafter, the reaction mixture was concentrated under reduced pressureto provide a residue. The residue was diluted with water (2 mL) to forma pale yellow solution, neutralized with 2N aqueous HCl (1.144 mL), andsonicated to provide a white precipitate. The precipitate was collectedby filtration, washed with water, and dried for 8 h under reducedpressure at 75° C. to provide 312 mg of Substituted-Quinoxaline-TypePiperidine Compound 361 as a colorless solid (yield 97%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 361,4-((endo)-8-((exo)-bicyclo[3.3.1]nonan-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 361: ¹H NMR: δ_(H) (400MHz, CDCl₃): 0.86 (m, 2H), 1.64 (m, 6H), 1.89 (m, 1H), 2.03 (dq, J=9.09,2.44 Hz, 2H), 2.42 (m, 9H), 3.01 (m, 2H), 3.49 (s, 1H), 4.26 (d, J=1.01Hz, 2H), 6.55 (s, 1H), 7.55 (t, J=7.33 Hz, 1H), 7.92 (dd, J=9.85, 5.81Hz, 1H), 8.18 (d, J=7.58 Hz, 1H), 8.40 (d, J=8.59 Hz, 1H), 11.41 (s,1H); LC/MS (100%, t_(r)=1.38 min): m/z=422.5 [M+H]⁺ (Calc: 421.5).

In a manner similar to that described above,Substituted-Quinoxaline-Type Piperidine Compounds 398 (yield 4% forthree steps) and 360 (yield 87%) were prepared from the compound offormula EC by using the compound of formula QI in place of the compoundof formula QA.

The identity of Substituted-Quinoxaline-Type Piperidine Compound 398,ethyl4-((endo)-8-((endo)-bicyclo[3.3.1]nonan-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 398: ¹H NMR: δ_(H) (400MHz, CDCl₃): 0.86 (dq, J=10.11, 2.69 Hz, 1H), 1.07 (m, 3H), 1.21-1.45(m, 10H), 1.65-2.37 (m, 15H), 3.67 (t, J=2.53 Hz, 2H), 4.50 (q, J=7.07Hz, 2H), 5.18 (br, 1H), 7.35 (t, J=7.33 Hz, 1H), 7.60 (t, J=9.60 Hz,2H), 7.91 (d, J=8.08 Hz, 1H); LC/MS: m/z=450.2 [M+H]⁺ (Calc: 449).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 360,4-((endo)-8-((endo)-bicyclo[3.3.1]nonan-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 360: ¹H NMR: δ_(H) (400MHz, CDCl₃): 0.84-0.88 (m, 4H), 1.38-1.46 (m, 1H), 1.54-1.65 (m, 3H),2.27 (m, 6H), 2.46 (dt, J=12.80, 4.93 Hz, 3H), 2.95 (br, 3H), 4.25 (s,2H), 6.61 (s, 1H), 7.51 (d, J=8.08 Hz, 1H), 7.88 (dd, J=9.60, 5.05 Hz,1H), 8.14 (d, J=8.59 Hz, 1H), 8.44 (d, J=4.04 Hz, 1H), 11.55 (s, 1H);LC/MS (100%, t_(r)=1.48 min): m/z=422.2 [M+H]⁺ (Calc: 421.5).

Alternatively the compound RB and compound 361 can be synthesized via analternative route, which is shown below:

In an alternative procedure, the intermediate (RA) can be converted tothe oxime using hydroxylamine hydrochloride and sodium acetate inethanol, and the oxime reduced to 8-exobicyclo[3.3.1]non-3-yl-8-endo-aza-bicyclo[3.2.1]oct-3-ylamine (RA′) byhydrogenation using platinum oxide in acetic acid under 5 atmospheres ofhydrogen. Intermediate (RA′) can be reacted with 2-fluoro nitrobenzeneand potassium carbonate in DMF to give8-exo-bicyclo[3.3.1]non-3-yl-8-endo-aza-bicyclo[3.2.1]oct-3-yl)-(2-nitro-phenyl)-amine(RA″). Finally reduction of the nitro group using 10% palladium oncharcoal can giveN-(exo-8-bicyclo[3.3.1]non-3-yl-8-endo-aza-bicyclo[3.2.1]oct-3-yl)benzene-1,2-diamine(RB).

5.44 Example 44

In a manner similar to the preparation of the compound of formula DC inExample 13, the compound of formula SA was prepared except that thecompound of formula EC was used in place of the compound of formula DBand memantine hydrochloride (i.e., the hydrochloride of1-amine-3,5-dimethyl-adamantane, Sigma-Aldrich) was used in place of1-adamantylamine (yield 5%).

The identity of the compound of formula SA,8-(3,5-dimethyl-adamantan-1-yl)-8-aza-bicyclo[3.2.1]octan-3-one, wasconfirmed using ¹H NMR.

Compound SA: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 3.95 (2H, m), 2.52 (2H, dd,J=16.7, 6.7 Hz), 2.28 (2H, dd, J=16.7, 3.3 Hz), 2.12 (1H, m), 1.80 (2H,m), 1.67-1.51 (9H, m), 1.37-1.23 (8H, m), 1.10 (2H, m), 0.86 (6H, s).

In a manner similar to the preparation of the compounds of formula DDand DE in Example 13, the compounds of formula SB and SC were preparedexcept that the compound of formula SA was Used in place of the compoundof formula DC (yield 85% of 1:1 SB:SC).

The identity of the compound of formula SB:SC endo:exo isomeric mixture,N-[8-3,5-dimethyl-adamantan-1-yl)-8-aza-bicyclo[3.2.1]oct-3-yl]-benzene-1,2-diamine,was confirmed using ¹H NMR.

Compounds SB:SC: ¹H NMR: δ_(H) (400 MHz, CDCl₃): 6.84-6.55 (4H, m), 3.90(1H, m, isomer 1 (SD), 3.80 (1H, m, isomer 2 (SC)), 3.69 (1H, m), 3.0(3H, bs), 2.41 (1H, m), 2.20-2.04 (3H, m), 1.95-1.76 (5H, m), 1.62 (2H,m), 1.50-1.05 (12H, m), 1.36 (3H, s, isomer 1 (SB)), 1.33 (3H, s, isomer2 (SC).

To the above SB:SC mixture (1.18 g, 3.1 mmol) and toluene (20 mL) wasadded acetic acid (0.2 mL, 3.41 mmol) followed by diethyl 2-oxomalonate(0.72 mL, 4.66 mmol). The reaction mixture was refluxed for 4 h, cooled,diluted with EtOAc (100 mL), washed with 1M aqueous K₂CO₃ solution (100mL), dried (MgSO₄), and evaporated to dryness under reduced pressure toprovide a yellow gum. Flash chromatography of the gum with a silica gelcolumn eluting with 400:100:10:1 hexanes:EtOAc:MeOH:ammonia provided 420mg of Substituted-Quinoxaline-Type Piperidine Compound 264 (yield 28%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 264,endo-N-[8-(3,5-dimethyl-adamantan-1-yl)-8-aza-bicyclo[3.2.1]oct-3-yl]-benzene-1,2-diamine,was confirmed by ¹H NMR and TLC.

Substituted-Quinoxaline-Type Piperidine Compound 264: ¹H NMR: δ_(H) (400MHz, CDCl₃): 7.92 (1H, dd, J=8, 1 Hz), 7.62 (1H, t, J=8 Hz), 7.53 (1H,J=8 Hz), 7.34 (1H, dt, J=8, 1 Hz), 4.50 (2H, q, J=8.9 Hz), 3.86 (1H, m),2.23 (4H, m), 2.12 (1H, m), 1.83 (4H, m), 1.46 (2H, m), 1.43 (3H, t,J=8.9 Hz), 1.26 (9H, m), 1.10 (2H, m), 0.86 (6H, s); TLC (SiO₂)400:100:10:1 hexanes:EtOAc:MeOH:ammonia: Rf=0.26 with UV detection,Dragendorffs reagent.

Further elution with 300:100:10:1 hexanes:EtOAc:MeOH:ammonia provided300 mg of Substituted-Quinoxaline-Type Piperidine Compound 265 (yield20%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 265,exo-N-[8-(3,5-dimethyl-adamantan-1-yl)-8-aza-bicyclo[3.2.1]oct-3-yl]-benzene-1,2-diamine,was confirmed by ¹H NMR and TLC.

Substituted-Quinoxaline-Type. Piperidine Compound 265: ¹H NMR: δ_(H)(400 MHz, CDCl₃): 8.34 (1H, bs), 7.91 (1H, dd, J=9.2, 1.2 Hz), 7.60 (1H,dt, J=9.2, 1.2 Hz), 7.33 (1H, dt, J=9.2, 1.2 Hz), 4.50 (2H, q, J=8 Hz),3.91 (2H, m), 2.63 (2H, t, J=16 Hz), 2.15 (1H, m), 1.88-1.72 96H, m),1.56 (4H, m), 1.52 (2H, m), 1.43 (3H, t, J=8 Hz), 1.37-1.24 (8H, m),1.13 (2H, m); TLC (SiO₂) 300:100:10:1 hexanes:EtOAc:MeOH:ammonia:Rf=0.19 with UV detection, Dragendorffs reagent.

Substituted-Quinoxaline-Type Piperidine Compound 266 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 264 in a manner similarto the preparation of Substituted-Quinoxaline-Type Piperidine Compound111 in Example 5 (yield 83%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 266,endo-8-aza-bicyclo[3.2.1]oct-3-yl]-3-oxo-3,4-dihydro-quinoxaline-2-carboxylicacid, was confirmed using ¹H NMR.

Substituted-Quinoxaline-Type Piperidine Compound 266: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 7.92 (1H, m), 7.80 (1H, m), 7.68 (1H, bs), 7.47 (1H, m),4.85 (1H, bs), 3.56 (2H, m), 2.49-2.12 (6H, m), 2.12-1.52 (15H, m), 1.35(2H, m).

5.45 Example 45

In a dry and argon-flushed 10 mL vial, CuBr (0.05 eq, Sigma-Aldrich) wassuspended in dry toluene (2.5 mL) and stirred at a temperature of about25° C. for 30 min. Thereafter, MS 4 Å molecular sieves (200 mg) wereadded, followed by 3-methylbut-1-yne (TB, 2.0 eq, Sigma-Aldrich),isobutyraldehyde (TA, 1.5 eq, Sigma-Aldrich), the hydrochloride ofSubstituted-Quinoxaline-Type Piperidine Compound 268 (200 mg, 1.0 eq),and TEA (1.2 eq). The resulting reaction mixture was warmed to 60° C.and shaken for 2 h. After the molecular sieves were filtered off, themixture was washed with diethyl ether and the filtrate was concentratedunder reduced pressure to provide a residue. The residue waschromatographed with a silica gel column eluted with 2:1 Et₂O:hexanes toprovide Substituted-Quinoxaline-Type Piperidine Compound 271, ethyl4-((endo)-8-(2,6-dimethylhept-4-yn-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate.

To a mixture of Substituted-Quinoxaline-Type Piperidine Compound 271 andEtOH (2 mL) at 0° C. was added 2N aqueous NaOH (0.3 mL). The resultingreaction mixture was stirred for 1 h as its temperature warmed from 0°C. to about 25° C. Thereafter, the reaction mixture was diluted withCHCl₃ (20 mL) and neutralized with 1N aqueous HCl. The organic portionwas separated, concentrated under reduced pressure, and dried to provide50 mg of the hydrochloride of Substituted-Quinoxaline-Type PiperidineCompound 272 as a white solid (yield 20% for two steps).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 272,4-((endo)-8-(2,6-dimethylhept-4-yn-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 272: ¹H NMR: δ_(H) (400MHz, CDCl₃): 11.4 (br, 1H, HCl), 8.38 (d, 1H, J=8.9 Hz), 8.14 (d, 1H,J=8.2 Hz), 7.83 (dd, 1H, J=7.2 Hz, 8.8 Hz), 7.48 (dd, 1H, J=8.1 Hz, 8.3Hz), 6.72-6.78 (m, 1H), 4.35-4.38 (m, 1H), 3.95-3.98 (m, 1H), 3.52-3.53(m, 1H), 3.0-3.08 (m, 2H), 2.18-2.6 (m, 8H), 1.25 (d, 3H, J=6.8 Hz),1.13-1.16 (m, 6H), 1.06 (d, 3H, J=6.6 Hz); LC/MS (100%, 0.4=5.897):m/z=423.6 [M+H]⁺.

Substituted-Quinoxaline-Type Piperidine Compound 273, ethyl4-((endo)-8-(6-methylhept-4-yn-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,was prepared from Substituted-Quinoxaline-Type Piperidine Compound 268by using propionaldehyde (Sigma-Aldrich) in place of isobutyraldehyde.Thereafter, in a manner similar to the preparation ofSubstituted-Quinoxaline-Type Piperidine Compound 272, the hydrochlorideof Substituted-Quinoxaline-Type Piperidine Compound 274 was preparedfrom Substituted-Quinoxaline-Type Piperidine Compound 273 (yield 30% fortwo steps).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 274,4-((endo)-8-(6-methylhept-4-yn-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 274: ¹H NMR: δ_(H) (400MHz, CDCl₃): 12.02 (br, 1H, HCl), 8.44 (d, 1H, J=8.3 Hz), 8.24 (dd, 1H,J=1.5 Hz, 8.2 Hz), 7.93-7.97 (m, 1H), 7.57-7.61 (m, 1H), 6.66-6.71 (m,1H), 4.55-4.58 (m, 1H), 4.09-4.13 (m, 1H), 3.54-3.59 (m, 1H), 3.02-3.14(m, 2H), 2.36-2.72 (m, 8H), 1.21-1.26 (m, 6H), 1.16 (t, 3H, J=7.5 Hz);LC/MS (100%, t_(r)=5.506): m/z=408.6 [M+H]⁺.

5.46 Example 46

In a manner similar to Example 15, Substituted-Quinoxaline-TypePiperidine Compound 280 was prepared from Substituted-Quinoxaline-TypePiperidine Compound 347 by using 3-aminoisonicotinonitrile(Sigma-Aldrich) in place of serine amide hydrochloride (yield 94%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 280,3-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)isonicotinonitrile,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 280: ¹H NMR: δ_(H)(CDCl₃): 10.38 (1H, s), 9.00 (1H, s), 8.44 (1H, t, J=2.50 Hz), 7.72 (1H,d, J=8.00 Hz), 7.53 (1H, d, J=8.60 Hz), 7.48 (1H, d, J=5.00 Hz), 7.40(1H, t, J=8.00 Hz), 7.32 (1H, t, J=8.00 Hz), 5.20 (1H, m), 3.69 (2H, s),2.31 (5H, m), 2.05 (2H, m), 1.85-1.50 m); LC/MS: m/z=483 [M+H]⁺ (Calc:482.6).

To a mixture of Substituted-Quinoxaline-Type Piperidine Compound 280(327 mg, 0.678 mmol), EtOH (4 mL), and water (2.0 mL) at a temperatureof about 25° C. was added the platinum catalyst complex UA (14.5 mg,0.034 mmol), prepared according to T. Ghaffar and A. W. Parkins,Tetrahedron Let., 36(47):8657-8660 (1995). The resulting reactionmixture was warmed to 80° C. and stirred for 8 h then concentrated underreduced pressure to provide a residue. The residue was chromatographedwith a silica gel column eluted with a gradient of from 97%:3%CHCl₃:MeOH to 90%:10% CHCl₃:MeOH to provide 298 mg ofSubstituted-Quinoxaline-Type Piperidine Compound 281 as a white solid(yield 88%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 281,3-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)isonicotinamide,was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 281: ¹H NMR: δ_(H)(DMSO-d₆): 11.76 (1H, s), 10.36 (1H, s), 8.49 (1H, s), 8.38 (1H, t,J=2.40 Hz), 7.97 (1H, s), 7.68 (2H, m), 7.44 (2H, m), 7.31 (1H, t,J=7.20 Hz), 5.20 (1H, br), 3.65 (2H, s), 2.50-1.90 (7H, m), 1.90-1.30(16H, m); LC/MS: m/z=501 [M+H]⁺ (Calc: 500.6).

To a mixture of Substituted-Quinoxaline-Type Piperidine Compound 281(150 mg, 0.300 mmol) and water (1.0 mL) at 0° C. was added concentratedaqueous HCl (2 mL, 65.8 mmol). The resulting reaction mixture was warmedto 80° C. and stirred for 3 h. Thereafter, upon neutralizing thereaction mixture with cold (0° C.) 2N aqueous NaOH a white precipitateformed. The precipitate was filtered, washed with water, washed withMeOH, and dried under reduced pressure to provide 80 mg ofSubstituted-Quinoxaline-Type Piperidine Compound 282 as a white solid(yield 53%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 282,3-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)isonicotinicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 282: ¹H NMR: δ_(H)(DMSO-d₆): 11.66 (1H, s), 10.54 (1H, s), 10.45 (0.9H, s) 9.60 (0.1H, m),8.44 (1H, d, J=5.00 Hz), 7.97 (2H, m), 7.70 (1H, d, J=8.00 Hz), 7.44(1H, t, J=8.00 Hz), 7.36 (1H, t, J=8.00 Hz), 5.96 (1H, m), 4.22 (2H, m),2.95 (1H, m), 2.70 (2H, m), 2.50-1.40 (20H, m); LC/MS (97%, t_(r)=1.35min): m/z=502 [M+H]⁺ (Calc: 501.6).

5.47 Example 47

In a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 281 in Example 46, Substituted-Quinoxaline-TypePiperidine Compound 275,2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)benzamide,was prepared except that 2-aminobenzonitrile was used in place of3-aminoisonicotinonitrile.

To a mixture of Substituted-Quinoxaline-Type Piperidine Compound 275(165 mg, 0.330 mmol) and water (4 mL) at 0° C. was added concentratedaqueous HCl (4 mL, 47.4 mmol). The resulting reaction mixture was warmedto a temperature of about 25° C. and stirred for 1 h. Thereafter, uponneutralizing the reaction mixture with cold (0° C.) 2N aqueous NaOH awhite precipitate formed. The precipitate was filtered, washed withwater, and dried under reduced pressure to provide 138 mg of thecompound of formula 276 as a white solid (yield 81%).

The identity of the compound of formula 276,5-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-5H-quinoxalino[2,1-b]quinazoline-6,12-dione,was confirmed using ¹H NMR and LC/MS.

Compound 276: ¹H NMR: δ_(H) (400 MHz, DMSO): 10.05 (0.8H, s), 9.34(0.2H, s), 8.77 (1H, d, J=8.0 Hz), 8.32 (1H, d, J=8.0 Hz), 7.98 (1H, t,J=8.0 Hz), 7.88 (1H, d, J=8.0 Hz), 7.71 (1H, t, J=8.0 Hz), 7.66 (1H, d,J=8.0 Hz), 7.50 (1H, t, J=8.0 Hz), 7.30 (1H, t, J=8.0 Hz), 5.48 (0.8H,m), 4.93 (0.2H, m), 4.26 (2H, m), 2.96 (1H, m), 2.76 (2H, m), 2.50-1.40(20H, m); LC/MS (97%, t_(r)=1.73 min): m/z=483 [M+H]⁺ (Calc: 482.3).

To a mixture of the compound of formula 276 (90 mg, 0.186 mmol) and MeOH(4 mL) at a temperature of about 25° C. was added 2N aqueous NaOH (1.86mL, 3.73 mmol). The resulting reaction mixture was warmed to atemperature of 80° C., stirred for 66 h, concentrated under reducedpressure, and diluted with water (5 mL) to precipitate a white solid.The precipitate was filtered and rinsed with water to provide 86 mg ofthe sodium salt of Substituted-Quinoxaline-Type Piperidine Compound 277(yield 88%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 277,2-(4-((endo)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-ylamino)benzoicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 277: ¹H NMR: δ_(H) (400MHz, DMSO-d₆): 14.48 (1H, s), 9.15 (1H, d, J=8.0 Hz), 8.02 (1H, d, J=8.0Hz), 7.55 (1H, d, J=8.0 Hz), 7.40 (1H, d, J=8.0 Hz), 7.30 (2H, m), 7.23(1H, d, J=8.0 Hz), 6.93 (1H, t, J=8.0 Hz), 5.10 (1H, br), 3.65 (2H, m),3.00 (1H, m), 2.50-1.40 (22H, m); LC/MS (100%, t_(r)=2.24 min): m/z=501[M+H]⁺ (Calc: 500.3).

5.48 Example 48

Under an argon atmosphere, a mixture of tert-butyl3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (VA, 9 g, 3B ScientificCorp., Libertyville, Ill.), 1,2-phenylenediamine (9 g), and sodiumtriacetoxyborohydride (20 g) was stirred at about 25° C. To thismixture, acetic acid (4 mL) was added and the resulting reaction mixturewas stirred at a temperature of about 25° C. for 5 h. The reactionmixture was quenched with water (20 mL) and MeOH (1 mL) to provide thecompound of formula VB, a mixture of the endo and exo isomers, whichmixture was used as follows. The organic portion was separated,concentrated under reduced pressure, and redissolved in toluene (100 mL)and AcOH (6 mL). To this, diethyl 2-oxomalonate (16 mL) at a temperatureof 0° C. was added, then the reaction mixture was warmed to 100° C. andstirred for 3 h. After cooling to about 25° C., the mixture was filteredover sea sand, washed with diethyl ether (50 mL), and concentrated underreduced pressure to provide a residue. Chromatography of the residuewith a silica gel column eluting with 1:1 hexanes:Et₂O provided 13.0 gof Substituted-Quinoxaline-Type Piperidine Compound 399, a mixture ofthe endo and exo isomers of ethyl4-(8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,as a brown oil. The oil was dissolved in 1,4-dioxane (150 mL), treatedwith 4N HCl in 1,4-dioxane (15 mL), and kept at 40° C. for 24 h. Thereaction mixture was concentrated under reduced pressure and titratedwith diethyl ether to provide 7.0 g of the hydrochloride ofSubstituted-Quinoxaline-Type Piperidine Compound 400, a mixture of theendo and exo isomers of ethyl4-(8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,as a white solid (yield 48% for three steps).

A reaction mixture of Substituted-Quinoxaline-Type Piperidine Compound400 (200 mg), 3-bromocyclohept-1-ene (VC, 2 eq), K₂CO₃ (1.0 g), TEA (1mL), and acetonitrile (4 mL) was shaken at 60° C. for 12 h. The reactionmixture was diluted with EtOAc (10 mL), filtered, and concentrated underreduced pressure to provide a residue. Chromatography of the residuewith a silica gel column eluting with 1:1 hexanes:Et₂O then 1:2hexanes:Et₂O provided 150 mg of Substituted-Quinoxaline-Type PiperidineCompound 401, ethyl4-((endo)-8-(cyclohept-2-enyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate,as an oil (yield 65%).

In a manner similar to the preparation of Substituted-Quinoxaline-TypePiperidine Compound 174 in Example 7, the hydrochloride ofSubstituted-Quinoxaline-Type Piperidine Compound 319 was prepared fromSubstituted-Quinoxaline-Type Piperidine Compound 401 (yield 64%).

The identity of Substituted-Quinoxaline-Type Piperidine Compound 319,4-((endo)-8-(cyclohept-2-enyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylicacid, was confirmed using ¹H NMR and LC/MS.

Substituted-Quinoxaline-Type Piperidine Compound 319: ¹H NMR: δ_(H) (400MHz, CDCl₃): 13.8 (br, 1H, COOH), 12.18 (br, 1H, HCl), 8.43 (d, 1H, 8.8Hz), 8.24 (dd, 11-1, 1.5 Hz, 8.2 Hz), 7.96 (ddd, 1H, 1.5, 7.2 Hz, 8.8Hz), 7.61 (ddd, 1H, 0.8, 8.1 Hz, 8.3 Hz), 6.6-6.68 (m, 1H), 6.12-6.24(m, 2H), 4.22-4.28 (m, 2H), 3.54-3.58 (m, 1H), 3.02-3.12 (m, 2H),2.42-2.55 (m, 4H), 2.32-2.36 (m, 2H), 2.18-2.24 (m, 2H), 2.06-2.12 (m,2H), 1.4-1.72 (m, 4H); LC/MS (100%, t_(r)=4.881 min): m/z=394.5 [M+H]⁺.

The compound of formula VC was prepared as follows:

A reaction mixture of cycloheptene (12 g, Sigma-Aldrich),N-bromosuccinimide (23 g, Sigma-Aldrich), and benzoyl peroxide (0.5 g,Sigma-Aldrich) in 100 mL of CCl₄ was heated at 80° C. for 2 h. Aftercooling to about 25° C., the mixture was filtered, washed twice withNaHCO₃ (40 mL for each wash), concentrated under reduced pressure, anddistilled at 40° C. under a pressure of 2 mmHg to provide 15 g of thecompound of formula VC as colorless oil.

5.49 Example 49 In Vitro ORL-1 Receptor Binding Assay

ORL-1 Receptor Binding Assay Procedures: Membranes from recombinantHEK-293 cells expressing the human opioid receptor-like receptor (ORL-1)(Receptor Biology) were prepared by lysing cells in ice-cold hypotonicbuffer (2.5 mM MgCl₂, 50 mM HEPES, pH 7.4) (10 mL/10 cm dish) followedby homogenization with a tissue grinder/Teflon pestle. Membranes werecollected by centrifugation at 30,000×g for 15 min at 4° C. and pelletsresuspended in hypotonic buffer to a final concentration 1-3 mg/mL.Protein concentrations were determined using the BioRad protein assayreagent with bovine serum albumen as a standard. Aliquots of the ORL-1receptor membranes were stored at −80° C.

Radioligand binding assays (screening and dose-displacement) used 0.1 nM[³H]-nociceptin (NEN; 87.7 Ci/mmole) with 10-20 μg membrane protein in afinal volume of 5004, binding buffer (10 mM MgCl₂, 1 mM EDTA, 5% DMSO,50 mM HEPES, pH 7.4). Non-specific binding was determined in thepresence of 10 nM unlabeled nociceptin (American Peptide Company). Allreactions were performed in 96-deep well polypropylene plates for 1 h atabout 25° C. Binding reactions were terminated by rapid filtration onto96-well Unifilter GF/C filter plates (Packard) presoaked in 0.5%polyethylenimine (Sigma). Harvesting was performed using a 96-welltissue harvester (Packard) followed by three filtration washes with 5004ice-cold binding buffer. Filter plates were subsequently dried at 50° C.for 2-3 hours. Fifty μL/well scintillation cocktail (BetaScint; Wallac)was added and plates were counted in a Packard Top-Count for 1 min/well.The data from screening and dose-displacement experiments were analyzedusing Microsoft Excel and the curve fitting functions in GraphPadPRISM™, v. 3.0, respectively, or an in-house function for one-sitecompetition curve-fitting.

ORL-1 Receptor Binding Data:

The Substituted-Quinoxaline-Type Piperidine Compounds will have abinding affinity (K) for the human ORL-1 receptor of about 1000 nM orless in one embodiment, or about 500 nM or less in another embodiment.Typically, the Substituted-Quinoxaline-Type Piperidine Compounds willhave a K_(i) (nM) of about 300 or less for binding to ORL-1 receptors.In one embodiment, the Substituted-Quinoxaline-Type Piperidine Compoundswill have a K_(i) (nM) of about 100 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave a K_(i) (nM) of about 35 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave a K_(i) (nM) of about 20 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave a K_(i) (nM) of about 15 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave a K_(i) (nM) of about 10 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave a K_(i) (nM) of about 4 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave a K_(i) (nM) of about 1 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave a K_(i) (nM) of about 0.4 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave a K_(i) (nM) of about 0.1 or less.

5.50 Example 50 In Vitro ORL-1 Receptor Functional Assay

ORL-1 Receptor [³⁵S]GTPγS Binding Assay Procedures:

Membranes from recombinant HEK-293 cells expressing the human opioidreceptor-like (ORL-1) (Receptor Biology) were prepared by lysing cellsin ice-cold hypotonic buffer (2.5 mM MgCl₂, 50 mM HEPES, pH 7.4) (10mL/10 cm dish) followed by homogenization with a tissue grinder/Teflonpestle. Membranes were collected by centrifugation at 30,000×g for 15min at 4° C., and pellets resuspended in hypotonic buffer to a finalconcentration of 1-3 mg/mL. Protein concentrations were determined usingthe BioRad protein assay reagent with bovine serum albumen as astandard. Aliquots of the ORL-1 receptor membranes were stored at −80°C.

Functional binding assays were conducted as follows. ORL-1 membranesolution was prepared by sequentially adding final concentrations of0.066 μg/μL ORL-1 membrane protein, 10 μg/mL saponin, 3 μM GDP and 0.20nM [35S]GTPγS to binding buffer (100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES,pH 7.4) on ice. The prepared membrane solution (190 μL/well) wastransferred to 96-shallow well polypropylene plates containing 10 μL of20× concentrated stock solutions of agonist/nociceptin prepared in DMSO.Plates were incubated for 30 min at about 25° C. with shaking. Reactionswere terminated by rapid filtration onto 96-well Unifilter GF/B filterplates (Packard) using a 96-well tissue harvester (Packard) and followedby three filtration washes with 200 μL ice-cold binding buffer (10 mMNaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plates were subsequently driedat 50° C. for 2-3 hours. Fifty μL/well scintillation cocktail(BetaScint; Wallac) was added and plates were counted in PackardTop-Count for 1 min/well. Data are analyzed using the sigmoidaldose-response curve fitting functions in GraphPad PRISM v. 3.0, or anin-house function for non-linear, sigmoidal dose-response curve-fitting.

ORL-1 Receptor Functional Data:

ORL-1 GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at an ORL-1 receptor.Substituted-Quinoxaline-Type Piperidine Compounds typically will have anORL-1 GTP EC₅₀ (nM) of about 5000 or less to stimulate ORL-1 receptorfunction. In one embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have an ORL-1 GTP EC₅₀ (nM) of about1000 or less. In another embodiment, the Substituted-Quinoxaline-TypePiperidine Compounds of the invention will have an ORL-1 GTP EC₅₀ (nM)of about 100 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave an ORL-1 GTP EC₅₀ (nM) of about 80 or less. In another embodiment,the Substituted-Quinoxaline-Type Piperidine Compounds of the inventionwill have an ORL-1 GTP EC₅₀ (nM) of about 50 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds of theinvention will have an ORL-1 GTP EC₅₀ (nM) of about 35 or less. Inanother embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have an ORL-1 GTP EC₅₀ (nM) of about 15or less. In another embodiment, the Substituted-Quinoxaline-TypePiperidine Compounds of the invention will have an ORL-1 GTP EC₅₀ (nM)of about 10 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have an ORL-1 GTPEC₅₀ (nM) of about 4 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have an ORL-1 GTPEC₅₀ (nM) of about 1 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have an ORL-1 GTPEC₅₀ (nM) of about 0.4 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have an ORL-1 GTPEC₅₀ (nM) of about 0.1 or less.

ORL-1 GTP Emax (%) is the maximal effect elicited by a compound relativeto the effect elicited by nociceptin, a standard ORL-1 agonist.Typically, the Substituted-Quinoxaline-Type Piperidine Compounds of theinvention will have an ORL-1 GTP Emax (%) of greater than about 50%. Inone embodiment, the Substituted-Quinoxaline-Type Piperidine CompoundSubstituted-Quinoxaline-Type Piperidine Compounds will have an ORL-1 GTPEmax (%) of greater than about 75%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have an ORL-1 GTPEmax (%) of greater than about 85%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have an ORL-1 GTPEmax (%) of greater than about 95%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have an ORL-1 GTPEmax (%) of about 100% or greater. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have an ORL-1 GTPEmax (%) of about 110% or greater. Typically, aSubstituted-Quinoxaline-Type Piperidine Compound of the invention actingas a partial agonist will have an ORL-1 GTP Emax (%) of less than about10%. In one embodiment, partial agonist Substituted-Quinoxaline-TypePiperidine Compounds will have an ORL-1 GTP Emax (%) of less than about20%. In another embodiment, partial agonist Substituted-Quinoxaline-TypePiperidine Compounds will have an ORL-1 GTP Emax (%) of less than about30%. In another embodiment, partial agonist Substituted-Quinoxaline-TypePiperidine Compounds will have an ORL-1 GTP Emax (%) of less than about40%. In another embodiment, partial agonist Substituted-Quinoxaline-TypePiperidine Compounds will have an ORL-1 GTP Emax (%) of less than about50%.

5.51 Example 51 In Vitro Mu-Opioid Receptor Binding Assays

μ-Opioid Receptor Binding Assay Procedures:

Radioligand dose-displacement binding assays for μ-opioid receptors used0.2 nM[³H]-diprenorphine (NEN, Boston, Mass.), with 5-20 mg membraneprotein/well in a final volume of 500 μL binding buffer (10 mM MgCl₂, 1mM EDTA, 5% DMSO, 50 mM HEPES, pH 7.4). Reactions were carried out inthe absence or presence of increasing concentrations of unlabelednaloxone. All reactions were conducted in 96-deep well polypropyleneplates for 1-2 hr at about 25° C. Binding reactions were terminated byrapid filtration onto 96-well Unifilter GF/C filter plates (Packard,Meriden, Conn.) presoaked in 0.5% polyethylemimine using a 96-welltissue harvester (Brandel, Gaithersburg, Md.) followed by performingthree filtration washes with 5004 of ice-cold binding buffer. Filterplates were subsequently dried at 50° C. for 2-3 hours. BetaScintscintillation cocktail (Wallac, Turku, Finland) was added (50 μL/well),and plates were counted using a Packard Top-Count for 1 min/well. Thedata were analyzed using the one-site competition curve fittingfunctions in GraphPad PRISM v. 3.0 (San Diego, Calif.), or an in-housefunction for one-site competition curve-fitting.

μ-Opioid Receptor Binding Data:

Typically, the Substituted-Quinoxaline-Type Piperidine Compounds willhave a K_(i) (nM) of about 3000 or less for binding to μ-opioidreceptors. In one embodiment, the Substituted-Quinoxaline-TypePiperidine Compounds will have a K_(i) (nM) of about 1000 or less. Inanother embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a K_(i) (nM) of about 650 or less.In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a K_(i) (nM) of about 525 or less.In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a K_(i) (nM) of about 250 or less.In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a K_(i) (nM) of about 100 or less.In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a K_(i) (nM) of about 10 or less.In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a K_(i) (nM) of about 1 or less. Inanother embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a K_(i) (nM) of about 0.1 or less.

5.52 Example 52 In Vitro Mu-Opioid Receptor Functional Assays

μ-Opioid Receptor Functional Assay Procedures:

[³⁵S]GTPγS functional assays were conducted using freshly thawedμ-receptor membranes. Assay reactions were prepared by sequentiallyadding the following reagents to binding buffer (100 mM NaCl, 10 mMMgCl₂, 20 mM HEPES, pH 7.4) on ice (final concentrations indicated):membrane protein (0.026 mg/mL), saponin (10 mg/mL), GDP (3 mM) and[³⁵S]GTPγS (0.20 nM; NEN). The prepared membrane solution (190 μL/well)was transferred to 96-shallow well polypropylene plates containing 104of 20× concentrated stock solutions of the agonist DAMGO ([D-Ala2,N-methyl-Phe4 Gly-ol5]-enkephalin) prepared in dimethyl sulfoxide(DMSO). Plates were incubated for 30 min at about 25° C. with shaking.Reactions were terminated by rapid filtration onto 96-well UnifilterGF/B filter plates (Packard, Meriden, Conn.) using a 96-well tissueharvester (Brandel, Gaithersburg, Md.) followed by three filtrationwashes with 200 μl of ice-cold wash buffer (10 mM NaH₂PO₄, 10 mMNa₂HPO₄, pH 7.4). Filter plates were subsequently dried at 50° C. for2-3 hr. BetaScint scintillation cocktail (Wallac, Turku, Finland) wasadded (50 μL/well) and plates were counted using a Packard Top-Count for1 min/well. Data were analyzed using the sigmoidal dose-response curvefitting functions in GraphPad PRISM v. 3.0, or an in-house function fornon-linear, sigmoidal dose-response curve-fitting.

μ-Opioid Receptor Functional Data:

μ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a μ-opioid receptor.Substituted-Quinoxaline-Type Piperidine Compounds typically will have aμ GTP EC₅₀ (nM) of about 5000 or less to stimulate μ-opioid receptorfunction. In one embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a μ GTP EC₅₀ (nM) of about 4100 orless. In one embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a μ GTP EC₅₀ (nM) of about 3100 orless. In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a μ GTP EC₅₀ (nM) of about 2000 orless. In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a μ GTP EC₅₀ (nM) of about 1000 orless. In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a μ GTP EC₅₀ (nM) of about 100 orless. In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds of the invention will have a μ GTP EC₅₀ (nM) of about 10 orless. In another embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds will have a μ GTP EC₅₀ (nM) of about 1 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds willhave a μ GTP EC₅₀ (nM) of about 0.4 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a μ GTP EC₅₀(nM) of about 0.1 or less.

μ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by DAMGO, a standard μ agonist. Typically, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave a μ GTP Emax (%) of greater than about 10%. In one embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a μ GTP Emax(%) of greater than about 20%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a μ GTP Emax(%) of greater than about 50%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a μ GTP Emax(%) of greater than about 65%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a μ GTP Emax(%) of greater than about 75%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a μ GTP Emax(%) of greater than about 88%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a μ GTP Emax(%) of about 100% or greater.

5.53 Example 53 In Vitro Kappa-Opioid Receptor Binding Assays

μ-Opioid Receptor Binding Assay Procedures:

Membranes from recombinant HEK-293 cells expressing the human kappaopioid receptor (kappa) (cloned in house) were prepared by lysing cellsin ice cold hypotonic buffer (2.5 mM MgCl₂, 50 mM HEPES, pH 7.4) (10mL/10 cm dish) followed by homogenization with a tissue grinder/Teflonpestle. Membranes were collected by centrifugation at 30,000×g for 15min at 4° C. and pellets resuspended in hypotonic buffer to a finalconcentration of 1-3 mg/mL. Protein concentrations were determined usingthe BioRad protein assay reagent with bovine serum albumen as astandard. Aliquots of kappa receptor membranes were stored at −80° C.

Radioligand dose displacement assays used 0.4-0.8 nM [³H]-U69,593 (NEN;40 Ci/mmole) with 10-20 μg membrane protein (recombinant kappa opioidreceptor expressed in HEK 293 cells; in-house prep) in a final volume of200 μL binding buffer (5% DMSO, 50 mM Trizma base, pH 7.4). Non-specificbinding was determined in the presence of 10 μM unlabeled naloxone orU69,593. All reactions were performed in 96-well polypropylene platesfor 1 h at a temperature of about 25° C. Binding reactions weredetermined by rapid filtration onto 96-well Unifilter GF/C filter plates(Packard) presoaked in 0.5% polyethylenimine (Sigma). Harvesting wasperformed using a 96-well tissue harvester (Packard) followed by fivefiltration washes with 200 μL ice-cold binding buffer. Filter plateswere subsequently dried at 50° C. for 1-2 hours. Fifty μL/wellscintillation cocktail (MicroScint20, Packard) was added and plates werecounted in a Packard Top-Count for 1 min/well.

κ-Opioid Receptor Binding Data: In one embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will havesubstantially activity at κ receptors. Typically, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 20,000 or less for κ receptors. In one embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 10,000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 5000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 1000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 500 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 300 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 100 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 50 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 20 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 15 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 10 or less.

5.54 Example 54 In Vitro Kappa-Opioid Receptor Functional Assays

κ-Opioid Receptor Functional Assay Procedures:

Functional [³⁵S]GTPγS binding assays were conducted as follows. Kappaopioid receptor membrane solution was prepared by sequentially addingfinal concentrations of 0.026 μg/μL kappa membrane protein (in-house),10 μg/mL saponin, 3 μM GDP and 0.20 nM [³⁵S]GTPγS to binding buffer (100mM NaCl, 10 mM MgCl₂, 20 mM IIEPES, pH 7.4) on ice. The preparedmembrane solution (1904/well) was transferred to 96-shallow wellpolypropylene plates containing 104 of 20× concentrated stock solutionsof agonist prepared in DMSO. Plates were incubated for 30 min at atemperature of about 25° C. with shaking. Reactions were terminated byrapid filtration onto 96-well Unifilter GF/B filter plates (Packard)using a 96-well tissue harvester (Packard) and followed by threefiltration washes with 200 μL ice-cold binding buffer (10 mM NaH₂PO₄, 10mM Na₂HPO₄, pH 7.4). Filter plates were subsequently dried at 50° C. for2-3 hours. Fifty 4/well scintillation cocktail (MicroScint20, Packard)was added and plates were counted in a Packard Top-Count for 1 min/well.

κ-Opioid Receptor Functional Data:

κ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a κ receptor.Substituted-Quinoxaline-Type Piperidine Compounds typically will have aκ GTP EC₅₀ (nM) of about 20,000 or less to stimulate κ opioid receptorfunction. In one embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds will have a κ GTP EC₅₀ (nM) of about 10,000 or less. Inanother embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds will have a κ GTP EC₅₀ (nM) of about 5000 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds willhave a κ GTP EC₅₀ (nM) of about 2000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 1500 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 800 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 500 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 300 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 100 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 50 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 25 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP EC₅₀(nM) of about 10 or less.

κ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by U69,593. Typically, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave a κ GTP Emax (%) of greater than about 10%. In one embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP Emax(%) of greater than about 15%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP Emax(%) of greater than about 30%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP Emax(%) of greater than about 40%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP Emax(%) of greater than about 45%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP Emax(%) of greater than about 75%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP Emax(%) of greater than about 90%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a κ GTP Emax(%) of about 100% or greater.

5.55 Example 55 In Vitro Delta-Opioid Receptor Binding Assays

δ-Opioid Receptor Binding Assay Procedures:

Radioligand dose-displacement assays used 0.2 nM [³H]-Naltrindole (NEN;33.0 Ci/mmole) with 10-20 μg membrane protein (recombinant delta opioidreceptor expressend in CHO-K1 cells; Perkin Elmer) in a final volume of500 μL binding buffer (5 mM MgCl₂, 5% DMSO, 50 mM Trizma base, pH 7.4).Non-specific binding was determined in the presence of 25 μM unlabelednaloxone. All reactions were performed in 96-deep well polypropyleneplates for 1 h at a temperature of about 25° C. Binding reactions weredetermined by rapid filtration onto 96-well Unifilter GF/C filter plates(Packard) presoaked in 0.5% polyethylenimine (Sigma). Harvesting wasperformed using a 96-well tissue harvester (Packard) followed by fivefiltration washes with 500 μL ice-cold binding buffer. Filter plateswere subsequently dried at 50° C. for 1-2 hours. Fifty μL/wellscintillation cocktail (MicroScint20, Packard) was added and plates werecounted in a Packard Top-Count for 1 min/well.

δ-Opioid Receptor Binding Data:

In one embodiment, the Substituted-Quinoxaline-Type Piperdine Compoundswill have substantially no activity at δ receptors. Typically, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 20,000 or less for δ receptors. In one embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 10,000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 7500 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 6500 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 5000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 3000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 2500 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 1000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 500 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 350 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 250 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 100 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a Ki (nM) ofabout 10 or less.

5.56 Example 56 In Vitro Delta-Opioid Receptor Functional Assays

δ-Opioid Receptor Functional Assay Procedures:

Functional [³⁵S]GTPγS binding assays were conducted as follows. Deltaopioid receptor membrane solution was prepared by sequentially addingfinal concentrations of 0.026 μg/μL delta membrane protein (PerkinElmer), 10 μg/mL saponin, 3 μM GDP and 0.20 nM [³⁵S]GTPγS to bindingbuffer (100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice. Theprepared membrane solution (190 μL/well) was transferred to 96-shallowwell polypropylene plates containing 10 μL of 20× concentrated stocksolutions of agonist prepared in DMSO. Plates were incubated for 30 minat a temperature of about 25° C. with shaking. Reactions were terminatedby rapid filtration onto 96-well Unifilter GF/B filter plates (Packard)using a 96-well tissue harvester (Packard) and followed by threefiltration washes with 200 μL ice-cold binding buffer (10 mM NaH₂PO₄, 10mM Na₂HPO₄, pH 7.4). Filter plates were subsequently dried at 50° C. for1-2 hours. Fifty μL/well scintillation cocktail (MicroScint20, Packard)was added and plates were counted in a Packard Top-count for 1 min/well.

δ-Opioid Receptor Functional Data:

δ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a δ receptor.Substituted-Quinoxaline-Type Piperidine Compounds typically will have aδ GTP EC₅₀ (nM) of about 20,000 or less to stimulate δ opioid receptorfunction. In one embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds will have a δ GTP EC₅₀ (nM) of about 10,000 or less. Inanother embodiment, the Substituted-Quinoxaline-Type PiperidineCompounds will have a δ GTP EC₅₀ (nM) of about 100 or less. In anotherembodiment, the Substituted-Quinoxaline-Type Piperidine Compounds willhave a δ GTP EC₅₀ (nM) of about 1000 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP EC₅₀(nM) of about 90 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP EC₅₀(nM) of about 50 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP EC₅₀(nM) of about 25 or less. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP EC₅₀(nM) of about 10 or less.

δ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by met-enkephalin. Typically, theSubstituted-Quinoxaline-Type Piperidine Compounds of the invention willhave a δ GTP Emax (%) of greater than about 10%. In one embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP Emax(%) of greater than about 30%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP Emax(%) of greater than about 50%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP Emax(%) of greater than about 75%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP Emax(%) of greater than about 90%. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP Emax(%) of about 100% or greater. In another embodiment, theSubstituted-Quinoxaline-Type Piperidine Compounds will have a δ GTP Emax(%) of about 110% or greater.

5.57 Example 57 Efficacy of Receptor Binding and Activity Response

The following Tables provide results on the efficacy of binding andactivity response of several Substituted-Quinoxaline-Type PiperidineCompounds to the ORL-1 receptor and, for certainSubstituted-Quinoxaline-Type Piperidine Compounds, the mu-opioidreceptor, the kappa-opioid receptor, and/or the delta-opioid receptor.

In Table 1, binding efficacy to the ORL-1 receptor was determined by theprocedure in Example 49. Binding efficacy to the mu-opioid receptor wasdetermined by the procedure in Example 51. Binding efficacy to thekappa-opioid receptor was determined by the procedure in Example 53.Binding efficacy to the delta-opioid receptor was determined by theprocedure in Example 55.

In Table 2, activity response to the ORL-1 receptor was determined bythe procedure in Example 50. Activity response to the mu-opioid receptorwas determined by the procedure in Example 52. Activity response to thekappa-opioid receptor was determined by the procedure in Example 54.Activity response to the delta-opioid receptor can be determined by theprocedure in Example 56.

TABLE 1 Efficacy of Receptor Binding of Substituted-Quinoxaline-TypePiperidine Compounds K_(i) [Average ± Std Deviation] (nM) Ref OpioidReceptor No. Compound ORL-1 Mu Kappa Delta 1 326.1 ±  13470 ±  7633734.6 1595 2 67.2 ± 2053 ± 257.0 ±   28064 112.0 343 122.0 3 153.7 ± 17060 ±  888 ± >10⁵ 7.0 12280 1173 4 117.5 ±  3869 ± 135.8 ±   8918±112.1 1724 115.0 2238 5 19.4 ± 4340 ± 22.5 ±  23220 12.5 1155 15.8 6 152 ± 1145 ± 165.2 ±   11122 125 1104 123.1 7  156 ± 1074 ± 296 ± 1961024 1182 45 8  322 ± 1634 ± 7556 ± 79 115 363 9 14.2 ± 1397 ± 167.6 ±  47271 13.3 1108 15.2 10 72.1 ± 1480 ± 73.5 ±  27675 19.1 120 118.2 11114.9 ±  1530 ± 905 ± 44071 24.2 185 177 12 20.9 ± 2391 ± 15.1 ±  5197413.9 261 2.2 13 96.5 ± 3278 ± 283 ± 43483 18.8 270 155 14  301 ± 3157 ±15188 29 197 15 15.4 ± 1199 ± 92.9 ±  24560 1.8 173 16.4 16

97.8 ± 5.0 2313 ± 247 328 ± 11.3 34024 17 181.8 ±  5254 ± 622 ± 378001.6 208 102 18  182 ± 2078 ± 303 ± 55229 29 57 9 19 16.8 ± 26627 11500±  545749 0.8 1090 20

 547 ± 90.0 21

74.8 ± 3.5 3396 ± 362 151 ± 20 22592 22

35.2 ± 2.3 3037 ± 579 30.4 ±  2.2 19407 23

60.8 ± 5.1 3942 ± 1253 514 ± 70 52099 24 27.0 ± 5281 ± 852 ± 60848 5.21532 61 25 65.7 ± 5979 ± 1300 ±  82251 10.0 937 360 26

 7.1 ± 0.3  629 ± 24 191.4 ±   30.4 35858 27

48.5 ± 7.0 2438 ± 493 583 ± 155.2 27790 28

156.3 ±  9.4 5244 ± 939 1038 ±  252 66315 29

39.8 ± 2.6 3780 ± 1098 481 ± 87 inactive 30

57.9 ± 1.3 1895 ± 309 378 ± 62.4 61698 31

36.9 ± 3.0 1488 ± 321 67.5 ±  7.6 34671 32

37.4 ± 7.5 6403 ± 1943 354 ± 28.2 548766 33

22.9 ± 4.9 3341 ± 1068 1282.6 ±   212.1 96003 34

 153 ± 36  627 ± 137 46.34 ±   5.96 26105 37

18.6 ± 3.7 2064 ± 346 222.01 ±   34.1 56989 38

 5.7 ± 1.3 1451 ± 313 375 ± 79.5 6673 39

 8.6 ± 1.9  624 ± 22 57.3 ±  7.43 52574 40

 309 ± 33 41

 426 ± 85 42

36.9 ± 4.5 1866 ± 27 611.9 ±   37.1 81321 43

42.3 ± 6.1  809 ± 57 544.2 ±   57 38851 44

 111 ± 24  513 ± 27 301 ± 68.4 45038 45

46.3 ± 3.0 3986 ± 1172 805 ± 97.4 46719 46

32.1 ± 3.7 1414 ± 337 191 ± 34.5 518930 47

42.4 ± 2.7 2368 ± 245 731 ± 55.1 >10⁵ 48

 355 ± 31 49

70.9 ± 7.2 1345 ± 153 971 ± 50.6 531427 50

35.2 ± 2.1  634 ± 28 59230 51

 4.0 ± 0.6  512 ± 79  22 ± 2.1 28106 52

  92 ± 16 3557 ± 1293 712 ± 177 43207 53

 332 ± 77 54

31.9 ± 4.8 5414 ± 591 1195 ±  151 528011 55

24.1 ± 7.0 2109 ± 765 929 ± 152 530892 56

36.5 ± 6.9 5056 ± 1453 544 ± 30.7 19145 57

  45 ± 13 1360 ± 468 379 ± 48.3 532394 58

14.8 ± 2.0  524 ± 107 175 ± 11.6 45883 59

29.9 ± 1.4 3183 ± 1005 457 ± 72 53164 60

 130 ± 29 6657 ± 2010 510 ± 125 38477 61

 130 ± 10 4412 ± 953 810 ± 170 28131 62

 368 ± 39 63

 438 ± 36 64

54.8 ± 1.3 9284 ± 2250 4359 ±  796 inactive 65

85.3 ± 4.5 3642 ± 704 1149 ±  121 85587 66

15.5 ± 1.3 1523 ± 106 587 ± 131 28211 67

19.1 ± 0.8 3296 ± 722 666 ± 74 86219 68

49.8 ± 3.7 6155 ± 354 1486 ±  180 54999 69

 4.2 ± 0.9  248 ± 33 161 ± 47 13091 70  109 ± 2511 ± 141 ± 13080 7 19310 71  111 ± 7426 ± 1034 ±  31727 6.7 254 232 72  220 ±  887 ± 23.4 ± 17 84 1.1 73 52.8 ± 7.5 74

12.6 ± 0.8  678 ± 9 630 ± 218 47391 75

 273 ± 13 76

 375 ± 115 77

10.9 ± 1.8 1239 ± 162 418 ± 42 21144 78

40.7 ± 4.1 1723 ± 313 618 ± 107 16831 79

  51 ± 12 2727 ± 260 994 ± 92 20971 80

13.7 ± 4.1  871 ± 196 132 ± 18 23741 81

  44 ± 12 2787 ± 843 669 ± 88 20507 82

16.2 ± 4.4 2144 ± 549 391 ± 71 15770 83

  44 ± 20 1918 ± 621 586 ± 97 10177 84

12.7 ± 0.5 1914 ± 277 245 ± 46 2712 ± 258 85 92.2 ± 4089 ± 182 ± 17850±  10.6 1450 26 3075 86 179.4 ±  6758 ± 83.5 ±  9670 ± 37.3 810 12.82065 87  338 ± 6 88

20.8 ± 4.3 1663 ± 590 536 ± 56 15584 89

75.2 ± 6.1 10180 ±  2530 4490 ±  1110 535200 90

6.42 ± 0.71 459.3 ±  8.9 253 ± 39 38310 91

5.54 ± 0.23 394.3 ±  4.2 224 ± 14 21860 92

41.2 ± 0.5 4650 ± 657 688 ± 189 34954 93

 299 ± 19 94

4.42 ± 0.43  819 ± 29 154 ± 19 25250 95

10.71 ±  0.64 5570 ± 981 2728 ±  785 53540 98  8.6 ±  196 ± 130 ± 292000.2 21 15 99  109 ± 1670 ± 657 ± 4470 ± 10 36 26 170 100  8.2 ± 1.2 101 1.6 ±  590 ± 14.9 ±  13970 0.2 47 2.0 102

 6.5 ± 0.5  576 ± 46 156 ± 20 49120 103

233.7 ±  7.8 6700 ± 700 4330 ±  700 26460 104 120.1 ±  12100 ±  5350 ± 29775 9.2 1315 1000 105  288 ± 39 106 61.4 ± 1172 ± 2840 ±  12882 7.3 35340 107  285 ± 33 108

607.4 ±  9.9 109  493 ± 34 110 1716 ±  177 111  189 ± 12825 ±  1925035615 16 600 112  500 ± 10 113  785 ± 72 114 52.1 ± 2510 ± 1203 ±  240721.0 65 200 115 23.8 ±  770 ± 998 ± 57741 0.9 55 92 116  836 ± 34 1171342 ±  71 118  561 ± 75 119 73.2 ± 3330 ± 381 ± >10⁵ 7.1 350 50 120 3.1 ±  210 ± 55.8 ±  1710 ± 0.3 16 6.3 340 121 18.9 ±  743 ± 460 ±13563 1.3 22 71 122  7.5 ± 373.7 ±  161 ± 17516 0.4 1.6 29 123 127.7 ± 2700 ± 743 ± 13745 8.0 250 148 124  103 ± 9840 ± 2600 ±  >10⁵ 10 422 165125 12.0 ± 391.0 ±  380 ± 42000 0.3 4.4 51 126 43.7 ±  422 ± 422 ± 259705.2 25 21 127  2.7 ±  188 ± 480 ± >10⁵ 0.4 19 80 128 15.7 ±  488 ± 250 ±17638 ±  2.4 60 15 320 129 13.5 ±  462 ± 180 ± 26095 1.1 30 13 130 11.9± 1320 ± 2430 ±  28211 1.1 270 578 131  275 ± 10 133

135.9 ±  13.6 1217 ± 115 501 ± 80 25020 168 >10⁵ 171 44.6 ± 2.3 226 20.4± 3200 ± 707 ± >10⁵ 4.0 125 51 228  4.4 ± 1083 ± 3320 ±  >20,000 1.4 61600 205  437 ± 36 207 39.6 ± 1300 ± 346 ± >20,000 5.7 57 62 209 78.8 ± 377 ± 534 ± 1870 2.6 36 62 188 16.3 ±  723 ± 871 ± 16400 2.0 126 90 18910.9 ± 644.2 ±  67.0 ±  11430 1.6 11.9 9.5 337

26.5 ± 1.6  706 ± 121 220.0 ±   7.7 8840 211 34.7 ±  713 ± 568 ± >20,0002.9 48 29 191 60.4 ± 1990 ± 1493 ±  37410 3.4 289 154 193 11.1 ± 6100 ±224 ± >20,000 0.3 56 21 212 14.6 ± 1140 ± 25.9 ±  >20,000 0.4 60 1.8 21810.6 ± 2530 ± 863 ± >20,000 0.5 270 45 194 158.0 ±  3920 ± 256 ± >20,0009.7 915 38 196 46.1 ± 5200 ± 1650 ±  8880 ± 1.4 370 203 970 221 16.8 ±10900 ±  740 ± >20,000 0.4 1150 145 197 74.5 ± 8900 ± 890 ± >20,000 5.7410 230 199 237.3 ±  >20,000 920 ± >20,000 8.4 360 201 44.8 ± 1600 ±1360 ±  2740 ± 1.8 260 170 850 216 15.8 ± 2250 ± 134 ± >20,000 1.1 53022 203  140 ± 1470 ± 750 ± >20,000 20 210 58 180  456 ± 74 305

 149 ± 23 4420 ± 250 780 ± 53 >20,000 174 71.4 ± 2918 ± 488 ± >20,0002.5 37 21 176 101.9 ±  4700 ± 1153 ±  1305 ± 4.5 238 165 39 178 10.60 ± 2807 ± 429 ± >20,000 0.02 307 75 277  538 ± 40 231 61.7 ± 11942 ±  2032±  547704 0.7 294 286 306

114.9 ±  16.8 1458 ± 173 350 ± 13 22330 307

 170 ± 24 1375 ± 182 478 ± 45 23090 308

77.5 ± 17.1  60.2 ± 5.8 144 ± 16 12160 309

62.9 ± 9.8  784 ± 43 210 ± 11 2045 310

127.6 ±  9.3  770 ± 37 229 ± 23 8680 311

24.6 ± 3.0  400 ± 48 49.3 ±  2.4 2570 240 40.3 ±  480 ± 46.3 ±  411903.3 40 3.8 312

35.9 ± 6.6  263 ± 11 172 ± 41 14500 313

35.8 ± 9.1  452 ± 49 35.3 ±  1.3 2220 241 17.7 ±  679 ± 440 ± 10900 3.669 79 253 131.4 ±  5300 ± 2055 ±  68750 9.2 900 427 257 1187 ±  103 248 911 ± 139 249  260 ± 46010 6000 ±  533100 14 2040 259  962 ± 62 255 400 ± 22 251 3294 ±  219 314

59.7 ± 4.1 1792 ± 112 909 ± 49 4925 153 22.2 ±  459 ± 66.0 ±  530900 1.818 15.6 261  596 ± 16 245  912 ± 72 243 1345 ±  67 247 89.9 ± 10970 3500±  533800 81 623 316

 632 ± 114 317

 157 ± 29 1160 ± 19 1720 ±  210 >20,000 272  740 ± 105 274  383 ± 45 27052.1 ± 2660 ± 1600 ±  >20 000 7.4 256 307 235 18.1 ± 14300 ±  1116±  >20,000 0.8 2650 18 318

60.8 ± 7.9 1930 ± 335 835 ± 83 7730 ± 255 319

 611 ± 78 320

15.4 ± 4.0 1865 ± 240 3090 ±  1300 15010 ±  380 321

>20,000 322

2841 ±  961 323

 205 ± 35 2800 ± 450 >20,000 >20,000 324

 398 ± 59 233  144 ± 37 325

  82 ± 24 266  4.1 ±  679 ± 1430 ±  >20,000 0.6 54 86 263 47.5 ± 395545625 ±  525570 6.1 1424 237 30.2 ± 16252 ±  2473 ±  524333 0.4 3179 85239 45.5 ± 57791 3272 ±  537763 4.4 398 326

24.6 ± 1.2 10098 16.2 ±  2.2 >20,000 279 29.9 ± 16913 447 ± >20,000 0.779 327

104.2 ±  5.8 37211 72.5 ±  182.5 >20,000 282  502 ± 1445 ± 64.2 ±  3220982 106 8.5 284 21.5 ± 8927 ± 223.4 ±   72511 1.5 524 12.1 328

 7.7 ± 0.1 3877 ± 261 102.0 ±   6.9 18818 ±  507 329

62.2 ± 7.5 7122 ± 605 31.2 ±  8.4 67102 330

66.1 ± 5.4 331

493.3 ±  60.2 332

587.2 ±  38.3 333 29.1 ± 17180 ±  5035 ±  39396 2.1 6501 984 334 38.1 ±4750 ± 6866 ±  16831 ±  7.2 262 1903 820 335

 8.6 ± 0.7 >20,000 5154 ±  809 >20,000 286  2.8 ± >20,000 16760±  >20,000 0.8 1446 288  1.8 ± 2060 ± 565 ± >20,000 0.3 199 62 336

 3.6 ± 0.6 3291 ± 186 365 ± 98 5437 ± 796 290  1.4 ±  699 ± 375 ± 3155 ±0.1 100 157 1282 292  8.5 ± 3429 ± 4470 ±  2141 ± 0.9 865 160 507 294 2.5 ±  709 ± 425 ± 1606 ± 0.1 94 112 155 299

 289 ± 15 300

 9.0 ± 1.5 443 63.4 ±  8.8  106 ± 30 296  4.8 ± 1029 ± 1547 ±  1970 ±0.9 108 604 259 298  2.0 ±  396 ± 469 ± 1523 ± 0.1 5.5 157 523 301

29.8 ± 4.0  487 ± 61 162 ± 35 1396 ± 241 302

 9.9 ± 0.8  160 ± 18 85.4 ±  18.8 2863 ± 334 303

35.4 ± 0.6  664 ± 79 1582 ±  393 1102 ± 456 304

13.8 ± 2.1  397 ± 71 523 ± 75  667 ± 232 222

30.2 ± 2.8 1862 ± 433 2889 ±  593 2027 ± 582 350  382 ± 74 351 33.5 ± 368 ± 129.5 ±   11275 3.3 97 14.4 352 11.5 ± 307.1 ±  49.7 ±  1743 ±1.3 4.0 3.8 57 353

22.9 ± 1.6  689 ± 64 589 ± 211 1159 ± 260 354

10.5 ± 2.2  292 ± 81 20.6 ±  1.1  386 ± 73 355

128.0 ±  7.9 5490 ± 85 3891 ±  920 >20,000 356

43.1 ± 3.4 1436 ± 215  76 ± 21 18180 357

 364 ± 18 358

 9.0 ± 1.1 1600 ± 55 640 ± 126 8900 ± 2390 359

11.6 ± 1.5  407 ± 33 1756 ±  308 1011 ± 239 360

202.8 ±  7.1 3825 ± 576 2691 ±  189 >20,000 361

 5.7 ± 0.4 4450 ± 1224 6143 ±  1617 >20,000 362  2.4 ± 1631 ± 2280 ± 4763 ± 0.2 77 213 509 363

 250 ± 22 14374 10240 ±  2400 7100 ± 1560 364

 1.4 ± 0.1  670 ± 220  63 ± 15  758 ± 95 365 1828 ±  123 366

50.0 ± 4.7 1759 ± 276 480.5 ±   26.5 2856 ± 763 367

 374 ± 73 368

 828 ± 126 369  178 ± 4032 ± 5345 ±  >20,000 17 1010 1725 370

1300 ±  50 371

 496 ± 68 372

 188 ± 17

TABLE 2 Activity Response of Substituted-Quinoxaline-Type PiperidineCompounds GTPγS (EC₅₀: nM, Emax: %) [mean ± SEM] Opioid Receptor RefORL-1 Mu Kappa No. EC₅₀ E_(max) EC₅₀ E_(max) EC₅₀ E_(max) 1 1850 ± 190 43 ± 1.7 2 580 ± 92 47.3 ± 2.0 2110 ± 424 14.7 ± 1.5 3 602 ± 95 51.7 ±3.7 4 1001 ± 105  83 ± 1.5 846 ± 80 30.5 ± 2.9 5 293 ± 47  73 ± 3.5  801± 208  13 ± 0.6 6  76 ± 74 85.3 ± 4.4 1643 ± 150 34.7 ± 1.7 7 979 ± 4067.3 ± 1.9  9777 ± 2022 14.7 ± 1.5 8  4560 ± 1120 55.7 ± 4.2 9 79.1 ±6.9  39 ± 1.5 1523 ± 153  12 ± 0.6 10 553 ± 59  34 ± 1.5 2227 ± 565 39.8± 4.8 11 900 ± 48 45.7 ± 1.8 12 452 ± 66 47.7 ± 3.5 1404 ± 86   28 ± 2.113 1690 ± 166 68.7 ± 2.4 14 4650 ± 238 54.7 ± 2.6 15 179 ± 24 93.7 ± 5.4794 ± 14 28.3 ± 3.2 16 3745 ± 93  61 ± 2 10810 ± 3960  16 ± 3.1 17  7871± 2230 100 ± 9  6663 ± 286   7 ± 1.2 18 1284 ± 84  69.0 ± 2.7 5125 ± 71628.3 ± 3.4 19 286 ± 30 115.3 ± 6.7  21 1466 ± 50  71.7 ± 1.2  460 ± 130 13 ± 1.2 22 440 ± 39  64 ± 3.6 690 ± 86  31 ± 1.2 23 950 ± 94 73.7 ±2.3 1896 ± 380 6.83 ± 0.6 24 611 ± 71  78 ± 2.3  7122 ± 1182 15.7 ± 2.625 781 ± 26  79 ± 2.5 26 108.6 ± 5.9  85.3 ± 2.7  2883 ± 1286 2076 ± 30217.3 ± 0.9 27 969 ± 89 92.3 ± 0.9 28 1880 ± 285 80.3 ± 1.2 29 468 ± 81 85 ± 0.6 3812 ± 747  8.25 ± 0.48 30 699 ± 19 92.7 ± 3.5  3967 ± 12039.67 ± 1.5 31 335 ± 32 76.3 ± 3.9 1400 ± 49  39.3 ± 2.0 32 406 ± 42  76± 0.6 7031 ± 662  29 ± 3.5 33 211 ± 21 71.3 ± 3.7 34 1077 ± 140  43 ±2.1  187 ± 41.6 26 ± 7 37 265 ± 31 97.7 ± 4.8 1499 ± 281  29 ± 5.1 3871.2 ± 8.1 119.7 ± 2.7   8763 ± 1214   7 ± 1.2 39  88 ± 30  78 ± 10 285± 54 12.7 ± 4.1 42 543 ± 27 86.3 ± 2.4  4367 ± 1002  8.67 ± 0.33 43 474± 67 88.3 ± 2.7  6439 ± 1518 1.77 ± 0.4 311.2 ± 39.6 12.67 ± 1.5  44392.2 ± 6.6   38 ± 3.8  8696 ± 3404  4 ± 1  980 ± 155 20.33 ± 1.9  45169 ± 58 98.7 ± 9.5 5331 ± 608  10 ± 0.6 46 399 ± 56 112.7 ± 2.3  4105 ±223  30 ± 1.5 47 418.7 ± 12.7 98.7 ± 4.4 3515 ± 466 10.67 ± 1.2  49  808± 110 76.3 ± 5.4 5398 ± 125 9.33 ± 0.7 50 367 ± 11  68 ± 2.5 689761   6± 4 51 49.1 ± 8.2  107 ± 3.1 6125 ± 419 2.33 ± 0.7 276 ± 42  11 ± 2.5 52957 ± 35  99 ± 4.6 2816 ± 93    9 ± 0.6 54 464 ± 28 100.3 ± 3.3  55 421± 50 106.7 ± 3.7   4862 ± 1205 9.33 ± 0.9 56 113 ± 11 48.7 ± 1.9 2545 ±960 14 ± 1 57 486 ± 34 85.3 ± 5.0  5238 ± 1981 12 ± 1 58 151.4 ± 7.9  96 ± 2.9 13779 ± 5344 4.67 ± 0.3  5930 ± 1751  13 ± 1.5 59 383 ± 63106.5 ± 3.8  5040 ± 774  12 ± 0.6 60 2137 ± 661 88.7 ± 6.3  6901 ± 102016.67 ± 0.7  61 1234 ± 238 73.3 ± 2.3  7826 ± 1712 7.67 ± 1.8 64 457 ±90 87.7 ± 2.3 65 348 ± 22 107.7 ± 3.3  66 107.6 ± 15.1 109.3 ± 5.4  3543 ± 1799 13.7 ± 1.2 67 84.9 ± 4.3 78.3 ± 3.8  6571 ± 1028 16.7 ± 0.368  478 ± 6.4  101 ± 5.9 70 788 ± 44 54.7 ± 1.3 2103 ± 403 12.7 ± 0.9 71 964 ± 116 65.3 ± 2.6 72 1479 ± 116 42.0 ± 2.9  297 ± 195 47.0 ± 1.2 73 377 ± 115 15.7 ± 1.7 74 184 ± 21 113.3 ± 3.3  4066 ± 137 10.0 ± 0.61222 ± 349 11.3 ± 1.5 77 97.8 ± 9.7  128 ± 4.7 78 363 ± 20 102.3 ± 5.7  3463 ± 1057 11.3 ± 1.3 79 703 ± 39 88.3 ± 2.4  3885 ± 1542 11.3 ± 1.281 469 ± 8  79.3 ± 3.2 1709 ± 376  4.7 ± 0.7 82 181.4 ± 9.8   102 ± 3.23019 ± 559 8 83 558 ± 77  79 ± 2.5 1981 ± 152 11.3 ± 1.5 84 182 ± 22105.3 ± 1.7  4013 ± 406 33.3 ± 0.9 85 197 ± 35 67.0 ± 3.2 3118 ± 525 22± 2 1936 ± 141 27.0 ± 1.7 86 422 ± 40 116.7 ± 7.4  529310  362 ± 54 11.8± 0.6 88 201 ± 27 110.7 ± 2.9  2278 ± 266  16 ± 0.6 89 806 ± 85 74.3 ±3.4 90  72.7 ± 13.7 104.7 ± 3.8   3569 ± 1391  9.7 ± 0.3 6001 ± 444  9.3± 1.4 91  51.7 ± 14.3 113.7 ± 2.0  6198 ± 677 16.3 ± 1.2 4145 ± 457 10.3± 0.9 92  510 ± 100 74.3 ± 6.0 2267 ± 101  3.3 ± 0.7 94 61.3 ± 5.6 113 ±8   7001 ± 3621  13 ± 2.1 1125 ± 434  17 ± 2.7 95  92 ± 14 103.3 ± 5.2 98 93.1 ± 8.3 83.3 ± 8.0 2150 ± 390 14   3150 ± 860 12.7 ± 2.7 99 1230 ±158 74.7 ± 4.5 >10⁵  0.7 ± 0.9 100 19.1 ± 3.6 29 ± 2 101 17.0 ± 4.2105.7 ± 5.0   4900 ± 2050  9.7 ± 0.7 32770   15.3 ± 4.1 102 103 ± 18112.3 ± 6.3   4500 ± 1500  8.7 ± 3.4  960 ± 167  5.7 ± 0.3 103 3240 ±400 73.7 ± 4.4 104 2428 ± 219 86.3 ± 5.2 106 400 ± 44 55.3 ± 5.8 1113024 ± 477  84 ± 10 114 924 ± 42 73 ± 2 115 43.6 ± 0.9 35.3 ± 2.3 1061 ±52  93   3512 ± 647 18 ± 2 119 3663 ± 171 62.0 ± 1.5 5997 ± 517 59.3 ±2.3 120 41.3 ± 4.2 94.0 ± 3.6 79340 831 ± 86  8.7 ± 0.3 121 265 ± 2789.7 ± 5.4 3485 ± 445  9.7 ± 1.2 2930 ± 132 10.7 ± 1.2 122 67.6 ± 3.087.3 ± 3.9  5111 ± 1661  8.7 ± 0.3 1365 ± 285  8.3 ± 0.9 123 2351 ± 369110.5 ± 6.5   3779 ± 1268  9.0 ± 1.2 124 1358 ± 89  115 ± 5  125 66.9 ±7.1 107.3 ± 2.4  3600 ± 825 10.8 ± 2.1 2560 ± 470 10.3 ± 1.8 126 594 ±83 105.0 ± 0.6  3580 ± 140 10.6 ± 1.2 4680 ± 975  8.3 ± 0.9 127 31.3 ±3.8 127.0 ± 5.3  1365 ± 250 12.5 ± 1.4 2450 ± 490 17   128 209 ± 31102.7 ± 2.7  1350 ± 125 12.0 ± 0.8 4340 ± 610 12.7 ± 1.5 129 182.6 ±7.5  107.7 ± 3.7  1750 ± 40   9.7 ± 0.6 3855 ± 572  8.3 ± 0.3 130 40.6 ±2.4 59.7 ± 0.3 336 ± 47 23 ± 1 133 473 ± 27 81.3 ± 3.0 1138 ± 281  9 ± 11138 ± 281  9 ± 1 226 357 ± 84 83  4567 ± 1257  7.7 ± 0.3 228 53.6 ± 8.4  101.3 207 946 ± 85 60 1943 ± 548  6.0 ± 1.5 209 1211 ± 54  69 1750 ±76  10.5  9700 ± 3550 3.7 188 103.7 ± 14.3   36.5 4940 ± 525 11.5  3340± 1590 3.3 189 175 ± 13 90 >20,000   21   >20,000    0.25 337 438 ± 1578 7120 ± 380  9.1 >20,000   10.7  211 337 ± 20 38 1080 ± 235  4.2 2260± 480 9   191 956 ± 67  67 ± 1.5 193  94.4 ± 19.0 34.5 ± 1.6  4727 ±1215  13 ± 2.1 212 195 ± 13 78.7 ± 3  382 ± 97  6.7 ± 1.8 218  85 ± 1753.7 ± 2.3  4839 ± 2411  9.7 ± 1.8 194 1760 ± 119 46.7 ± 1.9 >20,000  0   196 293 ± 23 40.3 ± 2.3 221 277.1 ± 5.6  80.3 ± 3.8 4458 ± 865  9.3± 1.3 197 517 ± 48 31.3 ± 1.8 5960 ± 561  7.7 ± 1.2 199 1774 ± 296 39 ±1 >20,000   0   201 1299 ± 240  84 ± 1.2 216 397 ± 26 81 ± 3 >20,000  0.3 203 3856 ± 15  73.3 ± 1.7  4587 ± 1293 6.3 305 394 ± 53 42.3 ±2.9 >20,000   1.0 174 1619 ± 224 69.7 ± 5.2 >20,000   0.3 176 1519 ± 10550.3 ± 4.4 178 125.0 ± 8.4  83.3 ± 5.4 3206 ± 379  6.3 ± 0.9 306 548 ±57 82.3 ± 3.7 2194 ± 744  5.7 ± 0.3 307 400 ± 72 54.0 ± 2.3 4787 ± 33611.3 ± 1.2 308 379 ± 58 97.7 ± 2.9 63410 10.3 ± 0.3 28900 24.7 ± 8.7 309 659 ± 155 92.7 ± 2.3 7780 ± 689 33.2 ± 4.3 24960 32.3 ± 9.2 310 419 ±62 81.3 ± 3.2 7406 ± 723 16.0 ± 1.7  8526 ± 2196 14.0 ± 6.7 311  78.6 ±12.5 74.7 ± 1.8 20640 14.0 28150 31.3 ± 3.8 240 103 ± 23 58.3 ± 1.9 9871 ± 1430  7.7 ± 0.6  6241 ± 2805 10.3 ± 5.3 312 138.2 ± 8.1  56.5 ±2.3 10896 ± 666  17.7 ± 0.7 11751 ± 4518 20.3 ± 2.6 313 269 ± 53  67 ±53 21190 12.3 ± 0.3  3946 ± 2100 12.0 ± 4.0 241 114 ± 16 87.3 ± 5.0 3922± 139 11.0 ± 0.6  450 ± 180  3.7 ± 0.3 253 3573 ± 302 67.8 ± 1.9 2494252 ± 181 95.8 ± 3.6 314 453 ± 66 61.0 ± 0.6  4425 ± 1516 10.3 ± 0.9153 210 ± 21 58.3 ± 1.6 643 ± 13  3.0 ± 0.4 667025   1.0 ± 2.0 247 271 ±16 33.3 ± 2.2 317 647 ± 27 58.3 ± 3.9 270 1016 ± 203 99.3 ± 1.3 235 207± 10 88 ± 5 318 236 ± 13  44 ± 1.7 2177 ± 656  6.7 ± 1.9 320 103.6 ±7.8   80 ± 4.8 233  503 ± 105 29 ± 3 325 109 ± 14  15 ± 1.2 266 33.8 ±1.0  80 ± 2.2 395.4 ± 43.3  6.6 ± 0.7 263 298 ± 26  69 ± 2.9 326 214 ±31 68 ± 3 429 ± 62 11.7 ± 0.3 279 471 ± 54 59 ± 2 >20,000    4.3 ± 1.3282 211.7 ± 0.9   58 ± 1.2 13444 ± 962  10.0 ± 1.2 284 618 ± 47 73.3 ±3.7 >20,000   8.0 ± 1  328 101.6 ± 5.2  75.3 ± 1.9  4397 ± 1592 15.0 ±2.5 329 321 ± 28 66.3 ± 2.4 552 ± 77 13.0 ± 1.7 330 75.4 ± 9.1  19 ± 1.5333 1831 ± 159 60.0 ± 1.7 334 293 ± 15 68.7 ± 3.4 335 174 ± 10 117 ± 5 286  17 ± 2.7 105.3 ± 5.7  288 11.6 ± 0.6  104 ± 4.6 >20,000    3.3 ±1.9 336 32.0 ± 5.0 80.3 ± 2.2 >20,000    6.0 ± 1.5 290 11.1 ± 1.0 96.5 ±1.9 3389 ± 838 17.3 ± 2.9 1770 ± 421 12.7 292 106.0 ± 3.8  97.5 ± 1.3294 28.1 ± 2.1 106.3 ± 0.9  5705 ± 574 14.7 ± 1.5 1258 ± 258 20.0 30053.1 ± 8.5 57.7 ± 2   5265 ± 1497  12 ± 1.8 208 ± 70  8.7 ± 1.3 301 208± 16 82.0 ± 2   6181 ± 1252 40.7 ± 3.2 1506 ± 494  10 ± 0.6 302 85 ± 498.3 ± 1.7 1365 ± 251  56 ± 6.5 1484 ± 367   7 ± 0.6 303 298 ± 23 90.0 ±2  5468 ± 552 45.7 ± 7.8 304 150 ± 6  102.7 ± 2.7  1727 ± 402 50.7 ± 2.93269 ± 939  6.7 ± 1.2 351 361 ± 58 53.3 ± 0.6 36425 20.0 ± 0.6 46490  63± 11 352 199 ± 40 80.0 ± 1.7 1727 ± 321  8.9 ± 0.5 3734 ± 971 13.0 ± 2.3353 219 ± 20 57.0  6980 ± 1255 31.7  7660 ± 1140 20.0 354 37.55 ± 1.3187.0 1409 ± 248 21.7 >20,000    5.3 355 1855 ± 414 74.7 ± 3.8 356 686 ±41 93.3 ± 8  >20,000    3.3 ± 1.2 358  62.6 ± 14.1 101.3 ± 5.7  1960 ±806 11.7 ± 2.3 359 133.7 ± 2.7  89.7 ± 5.2 3615 ± 730 28.7 ± 1.2 3601667.1 ± 18.4  57.3 ± 4.1 361 57.2 ± 3.1 58.7 ± 2.4 362  4.0 ± 0.9 47.8363  4088 ± 1164 67.0 ± 5.8 364  9.22 ± 0.44 61.8 571.8  9.5 >20,000   9.8 366  925 ± 101 86.5 ± 2.6 1169 ± 368 30.3 369 545 ± 85 37.7 ± 0.7372 214 ± 57 20.7 ± 3.8

5.58 Example 58 In Vivo Assays for Prevention or Treatment of Pain

Test Animals:

Each experiment uses rats weighing between 200-260 g at the start of theexperiment. The rats are group-housed and have free access to food andwater at all times, except prior to oral administration of aSubstituted-Quinoxaline-Type Piperidine Compound when food is removedfor 16 hours before dosing. A control group acts as a comparison to ratstreated with a Substituted-Quinoxaline-Type Piperidine Compound. Thecontrol group is administered the carrier for theSubstituted-Quinoxaline-Type Piperidine Compound. The volume of carrieradministered to the control group is the same as the volume of carrierand Substituted-Quinoxaline-Type Piperidine Compound administered to thetest group.

Acute Pain:

To assess the actions of a Substituted-Quinoxaline-Type PiperidineCompound for the treatment or prevention of acute pain, the rat tailflick test can be used. Rats are gently restrained by hand and the tailexposed to a focused beam of radiant heat at a point 5 cm from the tipusing a tail flick unit (Model 7360, commercially available from UgoBasile of Italy). Tail flick latencies are defined as the intervalbetween the onset of the thermal stimulus and the flick of the tail.Animals not responding within 20 seconds are removed from the tail flickunit and assigned a withdrawal latency of 20 seconds. Tail flicklatencies are measured immediately before (pre-treatment) and 1, 3, and5 hours following administration of a Substituted-Quinoxaline-TypePiperidine Compound. Data are expressed as tail flick latency(s) and thepercentage of the maximal possible effect (% MPE), i.e., 20 seconds, iscalculated as follows:

${\% \mspace{14mu} {MPE}} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {latency}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {latency}} \right)} \right\rbrack}{\left( {20\mspace{11mu} s\mspace{14mu} {pre}\text{-}{administration}\mspace{14mu} {latency}} \right)} \times 100}$

The rat tail flick test is described in F. E. D'Amour et al., “A Methodfor Determining Loss of Pain Sensation,” J. Pharmacol. Exp. Ther.72:74-79 (1941).

Inflammatory Pain:

To assess the actions of a Substituted-Quinoxaline-Type PiperidineCompound for the treatment or prevention of inflammatory pain, theFreund's complete adjuvant (“FCA”) model of inflammatory pain was used.FCA-induced inflammation of the rat hind paw is associated with thedevelopment of persistent inflammatory mechanical hyperalgesia andprovides reliable prediction of the anti-hyperalgesic action ofclinically useful analgesic drugs (L. Bartho et al., “Involvement ofcapsaicin-sensitive neurons in hyperalgesia and enhanced opioidantinociception in inflammation,” Naunyn-Schmiedeberg's Archives ofPharmacol. 342:666-670 (1990)). The left hind paw of each animal wasadministered a 50 μL intraplantar injection of 50% FCA. 24 hour postinjection, the animal was assessed for response to noxious mechanicalstimuli by determining the PWT, as described below. Rats were thenadministered a single injection of 1, 3, 10 or 30 mg/kg of either aSubstituted-Quinoxaline-Type Piperidine Compound; 30 mg/kg of a controlselected from Celebrex, indomethacin or naproxen; or carrier. Responsesto noxious mechanical stimuli were then determined 1, 3, 5 and 24 hourspost administration. Percentage reversal of hyperalgesia for each animalwas defined as:

${\% \mspace{14mu} {Reversal}} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)} \right\rbrack}{\left\lbrack {\left( {{baseline}\mspace{14mu} {PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)} \right\rbrack} \times 100}$

Assessments of the actions of the Substituted-Quinoxaline-TypePiperidine Compounds that were tested revealed these compounds wereefficacious, e.g., Substituted-Quinoxaline-Type Piperidine Compoundssignificantly reduced FCA-induced thermal hyperalgesia, with ED₅₀ valuesof from about 0.1 mg/kg to about 20 mg/kg and maximum % reversal valuesof from about 20% to about 100%. For example, forSubstituted-Quinoxaline-Type Piperidine Compound 241 the ED₅₀ value forreversal of thermal hyperalgesia was 2.7 mg/kg at 1 hour afteradministration, 3.8 mg/kg at 3 hours after administration, and 2.3 mg/kgat 5 hours after administration of Substituted-Quinoxaline-TypePiperidine Compound 241. Additionally, the maximum % reversal of thermalhyperalgesia was about 80% at 3 hours after administration ofSubstituted-Quinoxaline-Type Piperidine Compound 241. And, forSubstituted-Quinoxaline-Type Piperidine Compound 74 the ED₅₀ value forreversal of thermal hyperalgesia was 8.5 mg/kg at 1 hour afteradministration, 4.0 mg/kg at 3 hours after administration, and 7.8 mg/kgat 5 hours after administration of Substituted-Quinoxaline-TypePiperidine Compound 74. Additionally, the maximum % reversal of thermalhyperalgesia was about 80% at 3 hours after administration ofSubstituted-Quinoxaline-Type Piperidine Compound 74.

Moreover, for the Substituted Quinoxaline-Type Piperidine Compound 362,the ED₅₀ value for reversal of thermal hyperalgesia was 0.8 mg/kg at 1hour after administration, 1.5 mg/kg at 3 hours after administration,and 3.0 mg/kg at 5 hours after administration of SubstitutedQuinoxaline-Type Piperidine Compound 362. Additionally, the % reversalof thermal hyperalgesia after administration of a 3 mg/kg dose was 86%at 1 hour after administration, 51% at 3 hours after administration, and27% at 5 hours after administration of Substituted Quinoxaline-TypePiperidine Compound 362. And, for Substituted Quinoxaline-TypePiperidine Compound 361, upon administration of a 5 mg/kg dose, the %reversal of thermal hyperalgesia was 36% reversal at 1 hour afteradministration, 90% reversal at 3 hours after administration, and 70%reversal at 5 hours after administration of Substituted Quinoxaline-TypePiperidine Compound 361. And, for Substituted Quinoxaline-TypePiperidine Compound 358, upon administration of 5 mg/kg dose, the %reversal of thermal hyperalgesia was 34% reversal at 1 hour afteradministration, 46% reversal at 3 hours after administration, and 79%reversal at 5 hours after administration of Substituted Quinoxaline-TypePiperidine Compound 358.

Substituted Quinoxaline-Type Piperidine Compounds 358, 361, and 362 alsohave surprisingly and desirably reduced abnormal behavioral sideeffects, such as reduced sedation, hyperactivity and/or hypoactivity.Additionally and surprisingly, Substituted Quinoxaline-Type PiperidineCompound 362 has reduced cardiovascular side effects. These side effectswere determined using known methods: an in vitro hERG (human ethera-go-go gene) assay as disclosed in Z. Zhou et al., “Properties of HERGChannels Stably Expressed in HEK 293 Cells Studied at PhysiologicalTemperature,” Biophysical J. 74:230-241 (1998); and APD (actionpotential duration) in guinea pig purkinje fibers as disclosed in J. A.Hey, “The Guinea Pig Model for Assessing Cardiotoxic Proclivities ofSecond Generation Antihistamines,” Arzneimittelforschung 46(8):834-837(1996).

Neuropathic Pain:

To assess the actions of a Substituted-Quinoxaline-Type PiperidineCompound for the treatment or prevention of neuropathic pain, either theSeltzer model or the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats (Z.Seltzer et al., “A Novel Behavioral Model of Neuropathic Pain DisordersProduced in Rats by Partial Sciatic Nerve Injury,” Pain 43:205-218(1990)). Partial ligation of the left sciatic nerve is performed underisoflurane/O₂ inhalation anaesthesia. Following induction of anesthesia,the left thigh of the rat is shaved and the sciatic nerve exposed athigh thigh level through a small incision and is carefully cleared ofsurrounding connective tissues at a site near the trocanther just distalto the point at which the posterior biceps semitendinosus nerve branchesoff of the common sciatic nerve. A 7-0 silk suture is inserted into thenerve with a ⅜ curved, reversed-cutting mini-needle and tightly ligatedso that the dorsal ⅓ to ½ of the nerve thickness is held within theligature. The wound is closed with a single muscle suture (4-0 nylon(Vicryl)) and vetbond tissue glue. Following surgery, the wound area isdusted with antibiotic powder. Sham-treated rats undergo an identicalsurgical procedure except that the sciatic nerve is not manipulated.Following surgery, animals are weighed and placed on a warm pad untilthey recover from anesthesia. Animals are then returned to their homecages until behavioral testing begins. The animal is assessed forresponse to noxious mechanical stimuli by determining PWT, as describedbelow, prior to surgery (baseline), then immediately prior to and 1, 3,and 5 hours after drug administration for rear paw of the animal.Percentage reversal of neuropathic hyperalgesia is defined as:

${\% \mspace{14mu} {Reversal}} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)} \right\rbrack}{\left\lbrack {\left( {{baseline}\mspace{14mu} {PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)} \right\rbrack} \times 100}$

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anaesthesia. Following induction of anaesthesia, a 3 cmincision is made and the left paraspinal muscles are separated from thespinous process at the L₄-S₂ levels. The L₆ transverse process iscarefully removed with a pair of small rongeurs to identify visually theL₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) isisolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is notmanipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered aSubstituted-Quinoxaline-Type Piperidine Compound for the left rear pawof the animal. The animal can also be assessed for response to noxiousthermal stimuli or for tactile allodynia, as described below. The Chungmodel for neuropathic pain is described in S. H. Kim, “An ExperimentalModel for Peripheral Neuropathy Produced by Segmental Spinal NerveLigation in the Rat,” Pain 50(3):355-363 (1992).

Response to Mechanical Stimuli as an Assessment of MechanicalHyperalgesia:

The paw pressure assay can be used to assess mechanical hyperalgesia.For this assay, hind paw withdrawal thresholds (PWT) to a noxiousmechanical stimulus are determined using an analgesymeter (Model 7200,commercially available from Ugo Basile of Italy) as described in C.Stein, “Unilateral Inflammation of the Hindpaw in Rats as a Model ofProlonged Noxious Stimulation: Alterations in Behavior and NociceptiveThresholds,” Pharmacol. Biochem. and Behavior 31:451-455 (1988). Themaximum weight that can be applied to the hind paw is set at 250 g andthe end point is taken as complete withdrawal of the paw. PWT isdetermined once for each rat at each time point and either only theaffected (ipsilateral) paw is tested, or both the ipsilateral andcontralateral (non-injured) paw are tested.

Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia:

The plantar test can be used to assess thermal hyperalgesia. For thistest, hind paw withdrawal latencies to a noxious thermal stimulus aredetermined using a plantar test apparatus (commercially available fromUgo Basile of Italy) following the technique described by K. Hargreaveset al., “A New and Sensitive Method for Measuring Thermal Nociception inCutaneous Hyperalgesia,” Pain 32(1):77-88 (1988). The maximum exposuretime is set at 32 seconds to avoid tissue damage and any directed pawwithdrawal from the heat source is taken as the end point. Threelatencies are determined at each time point and averaged. Either onlythe affected (ipsilateral) paw is tested, or both the ipsilateral andcontralateral (non-injured) paw are tested.

Assessment of Tactile Allodynia:

To assess tactile allodynia, rats are placed in clear, plexiglasscompartments with a wire mesh floor and allowed to habituate for aperiod of at least 15 minutes. After habituation, a series of von Freymonofilaments are presented to the plantar surface of the left(operated) foot of each rat. The series of von Frey monofilamentsconsists of six monofilaments of increasing diameter, with the smallestdiameter fiber presented first. Five trials are conducted with eachfilament with each trial separated by approximately 2 minutes. Eachpresentation lasts for a period of 4-8 seconds or until a nociceptivewithdrawal behavior is observed. Flinching, paw withdrawal or licking ofthe paw are considered nociceptive behavioral responses.

The invention is not to be limited in scope by the specific embodimentsdisclosed in the examples that are intended as illustrations of a fewaspects of the invention and any embodiments that are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the scope of the appended claims.

A number of references have been cited, the entire disclosures of whichare incorporated herein by reference for all purposes.

What is claimed:
 1. A compound of Formula (IIE):

or a pharmaceutically acceptable salt thereof wherein: each R₂ isindependently: (a) -halo, —CN, —NO₂, —OT₃, —C(═O)T₃, —C(═O)OT₃,—C(═O)N(T₁)(T₂), —S(═O)₂OH, —S(═O)T₃, —S(═O)₂T₃, —S(═O)₂N(T₁)(T₂),—N(T₁)(T₂), —N(T₃)C(═O)T₃, —N(T₃)C(═O)N(T₁)(T₂), —N(T₃)S(═O)₂T₃, or—N(T₃)S(═O)₂N(T₁)(T₂); or (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl,—(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(5- or6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups; or (c) -phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5-or 6-membered)heteroaryl, each of which is unsubstituted or substitutedwith 1, 2 or 3 independently selected R₇ groups; a is an integerselected from 0, 1, and 2; each R₄ is independently: (a) —H; or (b)-halo, —CN, or —NO₂; or (c) —X, —(C₁-C₆)alkyl-X, -(5- or6-membered)heterocycle-X, or -(5- or6-membered)heterocycle-(C₁-C₆)alkyl-X; or (d) —C(═Y)CN, —C(═Y)X,—C(═Y)T₃, —C(═Y)YX, —C(═Y)YT₃, —C(═Y)N(T₁)(T₂), —C(═Y)N(R₉)CN,—C(═Y)N(R₉)X, —C(═Y)N(R₉)YH, —C(═Y)N(R₉)YX, —C(═Y)N(R₉)YCH₂X,—C(═Y)N(R₉)YCH₂CH₂X, or —C(═Y)N(R₉)S(═O)₂T₃; or (e) —N(R₉)X,—N(R₉)—CH₂X, —N(R₉)—CH₂CH₂X, —N(R₉)CH₂N(R₉)C(═N(R₁₂))N(R₁₂)₂,—N(R₉)—CH₂CH₂N(R₉)C(═N(R₁₂))N(R₁₂)₂, —N(T₁)(T₂), —N(T₃)C(═Y)T₃,—N(T₃)C(═Y)YT₃, —N(T₃)C(═Y)N(T₁)(T₂), —N(T₃)S(═O)₂T₃, or—N(T₃)S(═O)₂N(T₁)(T₂); or (f) —YH, —CH₂YH, —CH₂CH₂YH, —YX, or —YT₃; or(g) —S(═O)T₃, —S(═O)₂T₃, —S(═O)N(T₁)(T₂), —S(═O)₂N(T₁)(T₂), —S(═O)X, or—S(═O)₂X; X is: (a) —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,—(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,—(C₈-C₂₀)tricycloalkenyl, -(5- or 6-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with 1, 2 or 3 independently selected R₈ groups; or (b)-phenyl, -naphthalenyl, —(C₁₄)aryl, or -(5- or 6-membered)heteroaryl,each of which is unsubstituted or substituted with 1, 2 or 3independently selected R₇ groups; each Y is independently O or S; Z is—[(C₁-C₁₀)alkyl optionally substituted by R₁]_(h)—, wherein h is 0 or 1;or —(C₁-C₁₀)alkyl-NR₆C(═Y)—; each R₁ is independently: (a) -halo, —CN,—OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R₆)₇, —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV₁,or —C(═O)CN; or (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,—(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,—(C₈—C₂₀)tricycloalkenyl, or -(3- to 7-membered)heterocycle, each ofwhich is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₉ groups; or (c)

 or (d) -phenyl, -naphthalenyl, or —(C₁₄)aryl, each of which isunsubstituted or substituted with an R₇ group; or —Z—R₁ is3,3-diphenylpropyl- optionally substituted at the 3 carbon of the propylwith —CN, —C(═O)N(R₆)₂, —C(═O)OV₁, or -tetrazolyl; or —Z—R₁ is—(C₁-C₄)alkyl substituted with tetrazolyl; each R₅ is independently—(C₁-C₄)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR₉, —OR₉, —SR₉, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo, —N₃, —NO₂, —CH═N(R₉),—N(R₉)(C₁-C₆)alkyl-C(═O)OR₉, —N(R₉)₂, —N(R₉)OH, —N(R₉)S(═O)R₁₂,—N(R₉)S(═O)₂R₁₂, —N(R₉)C(═O)R₁₂, —N(R₉)C(═O)OR₁₂, —C(═O)R₉, —C(═O)OR₉,—OC(═O)R₉, —OC(═O)OR₉, —S(═O)R₉, or —S(═O)₂R₉; each R₆ is independently—H, —(C₁-C₆)alkyl, or —(C₃-C₇)cycloalkyl, or two R₆ groups attached tothe same nitrogen atom can together form a 5- to 8-membered ring,wherein the number of atoms in the ring includes the nitrogen atom, andin which one of the 5- to 8-membered ring carbon atoms is optionallyreplaced by O, S, or N(T₃); each R₇ is independently —(C₁-C₄)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —OR₉, —SR₉, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, -halo, —N₃, —NO₂, —CH═N(R₉), —N(R₉)₂, —N(R₉)OH,—N(R₉)S(═O)R₁₂, —N(R₉)S(═O)₂R₁₂, —N(R₉)C(═O)R₁₂, —N(R₉)C(═O)N(T₁)(T₂),—N(R₉)C(═O)OR₁₂, —C(═O)R₉, —C(═O)N(T₁)(T₂), —C(═O)OR₉, —OC(═O)R₉,—OC(═O)N(T₁)(T₂), —OC(═O)OR₉, —S(═O)R₉, or —S(═O)₂R₉; each R₈ isindependently —(C₁-C₄)alkyl, —(C₇-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR₉, —OR₉, —SR₉, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo, —N₃, —NO₂, —CH═N(R₉),—N(R₉)(C₁-C₆)alkyl-C(═O)OR₉, —N(R₉)₂, —N(R₉)OH, —N(R₉)S(═O)R₁₂,—N(R₉)S(═O)₂R₁₂, —N(R₉)C(═O)R₁₂, —N(R₉)C(═O)N(T₁)(T₂), —N(R₉)C(═O)OR₁₂,—C(═O)R₉, —C(═O)N(T₁)(T₂), —C(═O)OR₉, —OC(═O)R₉, —OC(═O)N(T₁)(T₂),—OC(═O)OR₉, —S(═O)R₉, or —S(═O)₂R₉; each R₉ is independently —H,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -benzyl, -(3- to 6-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂(halo); if h is 0, then R₁₁ can be —H,—CN, —C(═O)OR₉, or —C(═O)N(R₆)₂ or R₁₁ can be —(C₁-C₄)alkyl which isunsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂,—C(═O)OR₉, or —C(═O)N(R₆)₂; if h is 1, then R₁₁ can be —H, —CN, —OH,-halo, —C(═O)OR₉, or —C(═O)N(R₆)₂ or R₁₁ can be —(C₁-C₄)alkyl which isunsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂,—C(═O)OR₉, or —C(═O)N(R₆)₂; otherwise, wherein Z is—(C₁-C₁₀)alkyl-NR₆C(═Y)—, then R₁₁ can be —H, —CN, —C(═O)OR₉, or—C(═O)N(R₆)₂ or R₁₁ can be —(C₁-C₄)alkyl which is unsubstituted orsubstituted with —OH, —(C₁-C₄)alkoxy, —N(R₆)₂, —C(═O)OR₉, or—C(═O)N(R₆)₂; each R₁₂ is independently —H or —(C₁-C₄)alkyl; m is aninteger selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11; e and fare each an integer independently selected from 0, 1, 2, 3, 4, and 5provided that 2≦(e+≦5; j and k are each an integer independentlyselected from 0, 1, 2, 3, and 4 provided that 1≦(j+k)≦4; each p is aninteger independently selected from 0 and 1; each T₁ and T₂ isindependently —H or —(C₁-C₁₀)alkyl which is unsubstituted or substitutedwith 1, 2 or 3 independently selected R₅ groups and, optionally, inwhich any —(C₁-C₁₀)alkyl carbon atom except the carbon atom bondeddirectly to the atom to which T₁ or T₂ is attached is independentlyreplaced by O, S, or N(R₆), or T₁ and T₂ can together form a 5- to8-membered ring wherein the number of atoms in the ring includes thenitrogen atom to which T₁ and T₂ are bonded, said 5- to 8-membered ringis unsubstituted or substituted with 1, 2 or 3 independently selected R₅groups and, optionally, any carbon atom in said 5- to 8-membered ring isindependently replaced by O, S, or N(R₆); each T₃ is independently —H or—(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1, 2 or 3independently selected R₅ groups and, optionally, in which any—(C₁-C₁₀)alkyl carbon atom except the carbon atom bonded directly to theatom to which T₃ is attached is independently replaced by O, S, orN(R₁₂); each V₁ is independently —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,-phenyl, or benzyl; and each halo is independently —F, —Cl, —Br, or —I;provided that if Z is —[(C₁-C₁₀)alkyl optionally substituted by R₁]_(h)—and h is 0 then R₄ is not COOH.
 2. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein a is
 0. 3. Thecompound of claim 2 or a pharmaceutically acceptable salt thereof,wherein h is 0 and R₁ is:

wherein each R_(z) is independently —H, —(C₁-C₄)alkyl, —OH, or —CN. 4.The compound of claim 3 or a pharmaceutically acceptable salt thereof,wherein R₁ is optionally substituted bicyclo[3.3.1]nonyl.
 5. Thecompound of claim 3 or a pharmaceutically acceptable salt thereof,wherein R₁ is:


6. The compound of claim 5 or a pharmaceutically acceptable saltthereof, wherein each R_(z) is —H.
 7. The compound of claim 2 or apharmaceutically acceptable salt thereof, wherein R₄ is: (a) —C(═Y)YX;or (b) —N(R₉)X.
 8. The compound of claim 7 or a pharmaceuticallyacceptable salt thereof, wherein X of —N(R₉)X is —(C₁-C₆)alkylsubstituted with one R₈ group, -(5- or 6-membered)heterocyclesubstituted with one R₈ group, -phenyl substituted with one R₇ group, or-(5- or 6-membered)heteroaryl substituted with one R₇ group and each R₇or R₈ is —C(═O)OR₉.
 9. The compound of claim 7 or a pharmaceuticallyacceptable salt thereof, wherein each Y is O.
 10. The compound of claim2 or a pharmaceutically acceptable salt thereof, wherein R₄ is X and Xis -tetrazolyl.
 11. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof, wherein a is 1 and R₂ is selected from -halo.12. A method for modulating ORL-1 receptor function in a cell,comprising contacting a cell capable of expressing the ORL-1 receptorwith an effective amount of the compound or a pharmaceuticallyacceptable salt of the compound of claim
 1. 13. A method for treatingpain in an animal, comprising administering to an animal in need thereofan effective amount of the compound or a pharmaceutically acceptablesalt of the compound of claim
 1. 14. The compound of claim 1, whereinthe compound of Formula (IIE) is a compound of Formula (IIE1):

or a pharmaceutically acceptable salt thereof.
 15. The compound of claim14 or a pharmaceutically acceptable salt thereof, wherein a is
 0. 16.The compound of claim 15 or a pharmaceutically acceptable salt thereof,wherein h is 0 and R₁ is:

wherein each R_(z) is independently —H, —(C₁-C₄)alkyl, —OH, or —CN. 17.The compound of claim 16 or a pharmaceutically acceptable salt thereof,wherein R₁ is optionally substituted bicyclo[3.3.1]nonyl.
 18. Thecompound of claim 16 or a pharmaceutically acceptable salt thereof,wherein R₁ is:


19. The compound of claim 18 or a pharmaceutically acceptable saltthereof, wherein each R_(z) is —H.
 20. The compound of claim 15 or apharmaceutically acceptable salt thereof, wherein R₄ is: (a) —C(═Y)YX;or (b) —N(R₉)X.